TRANSCRIPTION FACTORS play a major role in differentiation in a number of cell types, including the various hematopoietic lineages.1-4 In the hematopoietic system, stem cells undergo a process of commitment to multipotential progenitors, which in turn give rise to mature blood cells. Although a number of transcription factors have been identified that play a role in the development of erythroid or lymphoid lineages,5-9 only in the past few years have those factors that influence development of myeloid cells been identified and studied. In particular, recent studies of the regulation of normal myeloid genes, as well as the study of leukemias, have suggested that transcription factors play a major role in both myeloid differentiation and leukemogenesis.10-12 To understand the process of normal myeloid differentiation, it is important to identify and characterize the transcription factors that specifically activate important genes in the myeloid lineage. These factors may play a role in acute myeloid leukemia (AML), in which this normal differentiation program is blocked. Finally, some of the transcription factor genes identified at the sites of consistent chromosome rearrangements in AML have now been shown to play a role in normal myeloid gene regulation.

The purpose of this review will be to summarize these recent data regarding myeloid gene regulation and the transcription factors mediating this process to understand normal myeloid development and leukemia. Emphasis will be placed on the identified or potential role of these factors in leukemia; we will focus on how alteration of myeloid transcription factors (changes in expression and structure) could lead to alterations in normal function in myelopoiesis, leading to a block in differentiation. In addition, we will discuss those factors that are involved in normal human myeloid maturation or human leukemia. Although this review will of necessity discuss different classes of factors, it does not aim to be an exhaustive compilation or listing of different factors and does not intend to be historical. Rather, it will attempt to highlight how recent findings can help to explain normal myeloid development and myeloid leukemia and will focus on certain examples to make important general points. In addition, this review will focus on early events in myeloid development and only briefly mention transcription factors involved in activation of mature myeloid cells. Finally, because there have been several recent reviews on hematopoietic factors in general, GATA, AML1, and the retinoic acid receptors, we will attempt as much as possible not to repeat what has been presented in these reviews.3,4 10-19 Some of the key issues that we will attempt to address in this review are the following: (1) How is gene expression restricted to myeloid cells? (2) How is the temporal expression of myeloid genes controlled? (3) Which transcription factors are thought to be necessary for myeloid development based on knockout and/or inactivation studies and which are thought to be necessary based on their redundancy? (4) If certain transcription factors are expressed in myeloid and nonmyeloid cells, why are certain target genes expressed in myeloid cells specifically? (5) How does a common progenitor cell become one type (myeloid) rather than another?

Currently, models have been advanced proposing that hematopoietic lineage determination is driven extrinsically (through growth factors, stroma, or other external influences),20,21 intrinsically (as described in stochastic models),22 or both.23 Our working hypothesis is that, regardless of whether the environmental or stochastic models are invoked, transcription factors are the final common pathway driving differentiation and that hematopoietic commitment to different lineages is driven by alternative expression of specific combinations of transcription factors, which often induce expression of growth factor receptors or growth factors. The transcription factors are often activated in positive autoregulatory loops, helping to explain the irreversible differentiation process found in human hematopoiesis. Experimental support of the hypothesis that transcription factors are the nodal decision points for myeloid differentiation include the observations that many genes cloned at the site of leukemic translocation breakpoints are transcription factors,11,12,24 genes isolated by their regulation of a phenotype (such as differentiation) are transcription factors,25 and, finally, knockouts of these transcription factors show gross defects in myeloid development.3 26-28 

Our understanding of myeloid factors has been brought about by a number of different methods. Initially, myeloid factors were identified by investigations of known transcription factors, particularly oncogenes; examples include myb, myc, and the homeobox genes.12a Similarly, a number of factors have been isolated using hybridization and/or polymerase chain reaction (PCR) methods based on similarity to known genes, such as MZF-1, with subsequent studies investigating the normal and forced expression of these factors in myeloid cells.29-36 A second approach is subtraction hybridization or differential screening, which identified Egr-1 as a potential mediator of monocytic development.25 A third method has been identification of factors through the analysis of myeloid-specific promoters. Examples are PU.1 and C/EBPα, and these studies will be described in further detail below. Finally, a number of myeloid transcription factors have been identified through their involvement in leukemias, either as a result of abnormal expression, such as PU.1,37,38 or through their involvement at the site of a consistent chromosome translocation (examples include AML139 and PLZF40; see Table 1).

Once identified, the role of these factors has been ascertained by a number of inhibitory studies. These include the use of antisense and competitor oligonucleotide techniques, which have shown the role of myc, myb, MZF-1, and PU.1 in myeloid development.41-44 A limited number of studies have used a trans-dominant mutant approach and have been used to demonstrate the role of the retinoic acid receptor α in myeloid development and of PU.1 in activation of specific gene targets.45-47 Finally, the technique of gene disruption (knockout) has recently been used to investigate the role of specific factors in myeloid development.3,7,26-29 48-50 A recent review has focused on the effects of these knockout studies on hematopoiesis in general3; therefore, we will discuss them only as they relate to myeloid transcription factors.

Many myeloid promoters appear to differ from what has been described previously for tissue-specific promoters.51 In general, a relatively small upstream region (usually a few hundred basepairs) is capable of directing cell-type–specific expression in tissue culture studies, although it appears that additional elements are necessary for position independent, high-level expression in a chromosomal locus (Fig 1). For example, almost all of the specificity and activity detected in transfection of tissue culture cells by the macrophage colony-stimulating factor (M-CSF) receptor, granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor α, and granulocyte colony-stimulating factor (G-CSF) receptor promoters are contained within 80, 70, and 74 bases of the major transcription start sites, respectively,52-54 and similar results have been obtained with the promoters for myeloid transcription factors such as PU.1.55,56 Although most of these promoters direct lineage and developmental specific expression, in general they lack a TATA box or defined initiator sequence. Interestingly, many myeloid promoters have a functional PU.1 binding site upstream of the transcription start site at a location corresponding to one similar to that of a TATA box. Because PU.1 can bind to the TATA binding protein (TBP) in vitro,57 one mechanism by which PU.1 could activate a whole class of myeloid promoters is by recruiting TBP, the primary component of the basal transcription factor TFIID, and the rest of the transcriptional apparatus. Consistent with this mechanism are studies showing that mutation of a PU.1 site in the FcγR1 promoter can abolish myeloid-specific expression, and replacement of this mutant site with a TATA box can restore myeloid expression.58 Other factors involved in myeloid gene regulation, including Sp1, C/EBPα, and Oct-1, have all been shown to interact with TBP,59-61 and these interactions could also help mediate recruitment of the basal transcription machinery. Finally, whereas some of these TATA-less and initiator-less myeloid promoters have multiple transcriptional start sites,55,62 others appear to have a single strong start site.63 64 The mechanism for how the start sites are determined in these promoters is unknown.

Fig. 1.

Specificity of the human M-CSF receptor promoter is mediated by combinatorial activity of factors in myeloid cells. The activity and specificity of the human M-CSF receptor promoter in transient transfection studies is mediated by the 50-bp region lying between bp −88 and −40 relative to the major transcription start site in monocytic cells.52,117,215 Shown are the binding sites for C/EBP, AML1, and PU.1, all of which are important for M-CSF receptor promoter activity. In the hematopoietic system, C/EBPα is myeloid specific, AML1 is expressed in all white blood cells, and PU.1 is B-cell– and myeloid-specific, so therefore the major cell type in which all three are expressed is myeloid cells. In addition, C/EBPα and AML1 can physically interact and synergize to activate this promoter.215 Others have shown using other promoters that C/EBP proteins can synergize with PU.1.88 Also shown is CBFβ, which forms a heterodimer with AML1 and augments its ability to bind to DNA.

Fig. 1.

Specificity of the human M-CSF receptor promoter is mediated by combinatorial activity of factors in myeloid cells. The activity and specificity of the human M-CSF receptor promoter in transient transfection studies is mediated by the 50-bp region lying between bp −88 and −40 relative to the major transcription start site in monocytic cells.52,117,215 Shown are the binding sites for C/EBP, AML1, and PU.1, all of which are important for M-CSF receptor promoter activity. In the hematopoietic system, C/EBPα is myeloid specific, AML1 is expressed in all white blood cells, and PU.1 is B-cell– and myeloid-specific, so therefore the major cell type in which all three are expressed is myeloid cells. In addition, C/EBPα and AML1 can physically interact and synergize to activate this promoter.215 Others have shown using other promoters that C/EBP proteins can synergize with PU.1.88 Also shown is CBFβ, which forms a heterodimer with AML1 and augments its ability to bind to DNA.

Close modal

Consistent with their lack of a TATA box, these promoters often are dependent on a functional Sp1 site, which can interact not only with the TATA binding protein, TBP, as well as a TBP-associated factor, TAF110.59 These Sp1 sites not only mediate activity, but also specificity and inducibility with differentiation.65-67 How the Sp1 factor mediates this specificity is not clear, but in one case Sp1 binds to its myeloid target in vivo in myeloid cells only,65 and in another, increased relative expression in myeloid cells of a phosphorylated form of Sp1 that shows markedly increased binding to its DNA target site is observed.66 Although Sp1 is ubiquitous, it is preferentially expressed in hematopoietic cells.68 Differential expression in distinct hematopoietic lineages has not been explored. In addition, Sp1 can mediate responses to retinoic acid, thyroid hormone, and retinoblastoma protein, all of which may influence myeloid differentiation.69-72 Finally, it has been recently shown that Sp1 belongs to a family of related factors and that at least one of these, Sp3, may mediate repression of target genes.73,74 Sp1 can also cooperate in repression with GATA-1,75 and this interaction could potentially repress myeloid targets in erythroid cells (see below).

Several of the myeloid promoters appear to have GATA sites that can bind GATA proteins specifically in gelshift assays. However, mutation of GATA binding sites in the CD11b76 or PU.155 promoters does not lead to significant loss of promoter function. Coexpression of either GATA-1 or GATA-2 leads to a slight downregulation (2-fold) of these promoters. Interestingly, there is a functional GATA-1 site in the promoter for the platelet-specific integrin IIb that is located at a position almost identical to that of the nonfunctional GATA site found in the myeloid integrin CD11b,77 suggesting evolutionary conservation of binding sites in related integrin promoters, but not function. The differences between the ability of GATA-1 to activate promoters such as IIb in erythroid or megakaryocytic cells, in which GATA-1 is thought to play an important role in lineage development and not in myeloid cells, may be due to cell-type–specific modifications of GATA and/or interactions with other transcription factors. In addition, GATA-1 is not expressed at significant levels in myeloid cells, and both GATA-144 and GATA-278 are downregulated in myeloid development. These results are consistent with the preservation of myeloid cell development in mice with targeted mutations of GATA-1.5 In contrast to monocytic and neutrophilic cells, high levels of GATA-1 are detected in eosinophils,79 but to date functional GATA sites have not been detected in eosinophil promoters. In summary, it appears that GATA proteins do not play an important positive role in myeloid development; indeed, downregulation may be critical for myeloid maturation.44,80 81 

As noted above, almost all myeloid promoters have a functional PU.1 site close to the transcription start site. There are a number of interesting exceptions to this rule. The CD14 promoter has a TATAA-like sequence and does not have a functional PU.1 site in its promoter.66 This promoter region is highly active and cell-type–specific in transient assays66 but not in transgenic mice.82,83 This scenario is somewhat similar to that of chicken lysozyme, which lacks a PU.1 site in its promoter but contains one in an enhancer located 2.7 kb upstream and which is part of a genomic fragment that is capable of high-level specific expression in mice.84 85 Whether other myeloid promoters that lack PU.1 sites will turn out to have PU.1-containing enhancer elements located several kilobases from the promoter remains to be determined.

Another set of myeloid genes that appear to have TATAA boxes are the primary granule protein promoters, including myeloperoxidase,86,87 neutrophil elastase,87,88 proteinase 3,89 and cathepsin G.90 At least three of these have been noted to have functional PU.1 sites, and in this class of genes PU.1 plays an important role, but perhaps has a different mechanism than other myeloid genes in which there is no TATAA box. At this point it is not clear what other common factors account for the distinct pattern of expression of these genes, in which mRNA is dramatically upregulated at the promyelocytic stage and then rapidly downregulated with further myeloid development. It has also been observed that a number of these same primary granule myeloid promoters (cathepsin G, myeloperoxidase, neutrophil elastase, aminopeptidase N, c-fes, and MRP8) contain a common sequence CCCCnCCC.91 Recently, a protein binding to this site has been described, and mutations of this site in the proteinase-3 promoter that abrogate binding of this factor lead to a significant loss in promoter function.89 Therefore, identification of this protein may lead to important understanding of the regulation of this whole family of myeloid genes.

In contrast to the primary granule protein genes, most other myeloid-specific genes are upregulated during the course of myeloid development and are expressed at highest levels in mature myeloid cells. Examples include key receptors, such as the G-CSF receptor92 and CD11b,93,94 as well as critical transcription factors, such as PU.1.44,95 In some cases, there are emerging clues into the mechanisms of upregulation during differentiation. For example, the upregulation of the CD14 promoter during vitamin D3-induced monocytic differentiation is mediated by an Sp1 site,67 and recently a novel transcription factor has been described that mediates upregulation of CD11b promoter activity during 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced differentiation of myeloid cell lines.96 The binding site for this factor is shared by the three leukocyte integrin promoters. The factor identified, MS-2, like Sp1, is not specific for myeloid cells. In other cases, the promoter elements and transcription factors mediating upregulation during myeloid differentiation have not been well defined. It should be noted that the transcription factors critical for upregulation during myeloid development versus those invoked during activation of mature myeloid cells may well be distinct. For example, the macrophage scavenger receptor has motifs mediating lineage specificity (including a PU.1 site) and a distinct element mediating upregulation of stimulated macrophages (through an AP-1/ets site).97 Similarly, distinct elements mediating lineage upregulation of the interleukin-1β (IL-1β) promoter in macrophage lines have been described.47,98 99 

Functionally important transcriptional regulatory elements have been described in the 5′ untranslated regions of a number of genes,100,101 and several myeloid promoters also contain important functional sites in their 5′ untranslated region. The human and murine PU.1 promoters are almost totally conserved in their 5′ untranslated region, and both contain a functional PU.1 site.55 In the case of the human and murine G-CSF receptor promoters, conservation in this region is mainly limited to the PU.1 site found there.53 

Often myeloid regulatory factors have been identified through the investigation of myeloid-specific promoter elements in studies involving transient transfection studies in tissue culture cell lines. In transgenic mice, other regulatory elements, such as locus control elements, are very important.102 A number of myeloid promoters have worked to some extent in transgenic studies involving the expression of heterologous genes in myeloid cells. In some instances, there is variability of levels of expression and significant position dependence. For example, the proximal 1.5 kb of the gp91-phox gene, normally expressed at high levels in granulocytes, targeted reporter expression to a small subset of monocytic cells only, and most monocytes and neutrophils did not express the transgene.103 In other examples, the responsible regulatory elements have not yet been defined in detail. These studies include human c-fes/fps,104 chicken lysozyme,85,105 or human cathepsin G,90 in which the investigators reported high-level, properly regulated transgene expression. In these studies, relatively large pieces of DNA (6 to 21.5 kb) were used that included the gene itself as the reporter. In some instances, the expression patterns of the transgenes were not described in detail, but were stated to be specific for macrophages and neutrophils, respectively. Examples include those involving a 5-kb portion of the monocytic M-CSF (CSF-1) receptor promoter, which was reported to target macrophages,106,107 and the MRP8 promoter, which was used to express bcl-2 in neutrophils.108 The MRP8 promoter has also been used to induce expression of a PML/RARα transgene in myeloid cells, resulting in a high percentage of expressing transgenic lines, altered granulocytic differentiation, and, in some animals, an acute leukemia resembling human acute promyelocytic leukemia.109 A recent study has shown that the human lysozyme promoter can direct reporter gene expression in macrophages.110 

A number of studies have looked at the ability of myeloid integrin promoters to direct the expression of reporter genes in transgenic studies.111,112 The CD11b promoter is capable of driving high-level expression of a reporter gene in myeloid cells at levels comparable to the endogenous CD11b promoter. This promoter construct is position-dependent, perhaps explaining why another group did not observe similar levels of expression.112 Although in these studies the activity of the promoter was highest in mature myeloid cells, this promoter construct has also been used to direct expression of the t(15:17) PML/RARα fusion protein in early myeloid cells.113 The reason for these differences is not clear, but may reflect a significant amount of position dependence on promoter activity and specificity. Attempts to direct expression of reporter genes into early myeloid cells using promoters such as CD3483 and c-kit114 have not been successful. However, recent reports suggest that upstream regions of the cathepsin G115 and MRP8108,109 genes may be useful in directing expression of an inserted cDNA into promyelocytes. Many of the promoters used in these studies, like most myeloid-specific genes, lack a TATAA box,63,76 and previous studies using transient transfections in tissue culture cells have shown the role of PU.1 in the myeloid specificity of the promoters (Table 2). Of the myeloid genes that have been shown to function in transgenic studies to date, several of them, including CD11b,116 the M-CSF receptor,117 the chicken lysozyme enhancer,84 and c-fes,118,119 have important functional PU.1 sites. A recent study has confirmed the importance of the PU.1 site in macrophage expression of the macrophage scavenger receptor.120 These studies strongly suggest that PU.1 will in general be a critical factor in directing myeloid expression in transgenic studies.

In summary, it appears from the transgenic studies that myeloid promoters can drive expression in monocytic and neutrophilic cells in transgenic mice and that the PU.1 site is likely to be critical. However, the details of the other critical elements necessary for myeloid-specific and position-independent expression are not defined yet, and much work needs to be performed in this area in the future.

An exciting prospect would be to use the myeloid regulatory elements to target given genes to proper hematopoietic compartments for gene therapy applications, particularly in terms of directing macrophage expression of enzymes involved in glycogen storage diseases.121 Myeloid promoter elements may be useful for viral vectors, especially adeno-associated virus (AAV), because, at least in transient assays, very small DNA fragments of a few hundred basepairs direct activity that is as high and as specific as much larger fragments. A note of caution is that larger elements or a combination of promoter and upstream elements (locus control regions) may be necessary, as noted above from the description of transgenic studies. Very few reports on the use of myeloid elements in gene therapy vectors have been reported. In one study, the CD11b promoter failed to direct significant reporter expression when incorporated into a retroviral vector,122 but a second study showed the same promoter directing significant amounts of glucocerebrosidase mRNA and enzymatic activity in myeloid cell lines and in bone marrow.123 Again, the reason for the discrepancies observed between these two studies using a similar promoter is not clear, and much more work needs to be performed in this area of research.

PU.1: A master regulator of myeloid genes.Recent studies have focused on PU.1 as a major regulator of myeloid development.26,44,161 PU.1 is the product of the Spi-1 oncogene identified as a consequence of its transcriptional activation in Friend virus-induced erythroleukemias.14,37,38,124 The role of PU.1 in the malignant transformation of the proerythroblast was confirmed by subsequent studies. Overexpression of PU.1 from a retroviral construct in long-term bone marrow cultures is able to stimulate the proliferation of proerythroblast-like cells that differentiate at a low frequency into hemoglobinized cells,125 and overexpression in transgenic mice can also induce erythroleukemia.126 Moreover, PU.1 antisense oligonucleotides reduce the capacity of Friend tumor cells to proliferate.127 Taken together, these data suggest that deregulation of PU.1 increases the self-renewal capacity of erythroid precursor cells and blocks their differentiation. Furthermore, it shows the importance of proper regulation of PU.1 in the hematopoietic system.

PU.1 is a member of the Ets transcription family.124 Ets factors all contain a characteristic DNA binding domain of approximately 80 amino acids.14,128,129 PU.1 and the related Ets family member Spi-B130 form a distinct subfamily within the larger group of Ets proteins, with very distinct structure, patterns of expression, binding specificity, and functions that are nonoverlapping with other members of the Ets family. The PU.1 protein consists of 272 amino acids, with the DNA binding domain located in the carboxyl terminal part of the protein, whereas the amino terminus contains an activation domain that has been implicated in interactions with other regulatory proteins.57,124,131,132 The structure of the DNA binding domain has been recently determined and demonstrates a winged helix-turn-helix motif.133 

PU.1 shows specific patterns of hematopoietic expression. PU.1 is expressed at highest levels in myeloid and B cells, but not in T cells.37,95,124 During hematopoietic development, PU.1 mRNA is expressed at low levels in murine ES cells and human CD34+ stem cells and is specifically upregulated with myeloid differentiation.44 The timing of this upregulation coincides with the first detection of early myeloid maturation, suggesting that this increase in expression may be an important process in myeloid development, and inhibition of PU.1 function at this juncture can block myeloid progenitor formation.44 These findings were confirmed by another report showing that PU.1 is expressed in the earliest Go CD34+ stem cells and upregulated as single CD34+/CD38 cells developed into myeloid colonies.134 Studies in both primary CD34+ cells and human leukemic cell line models suggest that PU.1 mRNA and DNA binding activity do not increase further with subsequent myeloid maturation from the promyelocytic to more mature stages,44,95 but these studies do not preclude the possibility that the high levels of mRNA observed in human monocytes and neutrophils95 are a result of subsequent final maturation and/or activation. Although initially thought to be B-cell and monocyte specific,124,135 high levels of both PU.1 mRNA and DNA binding activity have been subsequently found in neutrophils.95 PU.1 mRNA has also been detected in human eosinophils (S.J. Ackerman and D.G. Tenen, unpublished observations). In murine Friend erythroleukemia cells, PU.1 is downregulated during chemically induced erythroid differentiation.127,136 137 

These expression studies suggest that regulation of PU.1 mRNA may play a significant role in the commitment of early multipotential progenitors to the myeloid lineages, as well as in the further differentiation and maturation of these cells. Characterization of the murine and human PU.1 promoters shows that a highly conserved region surrounding the transcription start sites can direct myeloid-specific activity in transient transfection studies. The important functional sites identified thus far in the promoter, an octamer site at bp −54, an Sp1 site at bp −39, and a site for PU.1 itself at bp +20, are conserved in the two species. In B cells, the octamer site plays a major role in PU.1 expression,56,138 whereas in myeloid cells the PU.1 site is the most important for function of the promoter.55 This study suggests the presence of a positive feedback mechanism in the regulation of the PU.1 promoter similar to that shown for another Ets family member, Ets-1.139 Such autoregulation of transcription factors could play a major role in commitment and differentiation of hematopoietic multipotential progenitor cells (see below). The PU.1 promoter also contains a site that can bind GATA proteins, but no binding could be detected using nuclear extracts from myeloid cell lines, and cotransfection of either a GATA-1 or GATA-2 expression construct repressed the PU.1 promoter twofold. Important unanswered questions are whether GATA proteins affect PU.1 expression in multipotential progenitors44 or in early erythroid cells, in which PU.1 is repressed in the course of differentiation.136,137,140 Finally, although the elements described above direct expression of PU.1 in tissue culture cells, as much as 2 kb of upstream murine DNA sequence failed to direct expression of a reporter cDNA in spleen or peritoneal macrophages in transgenic studies, so other elements are required for high level expression in the chromosomal context.83 

PU.1, like other Ets factors,128 was first noted to bind to a sequence characterized by a purine-rich core (GGAA), hence its name.124 However, the DNA binding specificity of PU.1 appears to be quite distinct from that of other Ets factors. For example, PU.1 and Spi-B bind to the CD11b PU.1 site, but not the other Ets family members Ets-1, Ets-2, Elf-1, or Fli-1.44 In addition, it is not possible to predict PU.1 binding by observation of a 5′-GAGGAA-3′ sequence. For example, there are three such sequences in the M-CSF receptor promoter, and PU.1 does not bind to any of them with high affinity. Instead, PU.1 binds to the nearby sequence 5′-AAAGAGGGGGAGAG-3′.117 This example is consistent with previous work indicating that binding of PU.1 and other Ets factors is dependent on sequences outside the GGAA core.141 In addition, many functional PU.1 binding sites in myeloid promoters have a string of adenosine residues immediately 5′ of the GA core.54,116,117,137 These results are consistent with a recently described consensus sequence for PU.1 binding.118 The availability of an x-ray crystallographic structure for PU.1133 will assist in further studies of PU.1 binding specificity. In summary, PU.1 is distinct from other Ets factors in DNA binding specificity. Identification of the transactivation domain of PU.1 has been relatively difficult because PU.1 acts as a weak transactivator; indeed, most transactivation studies have required multiple PU.1 binding sites and used artificial promoter constructs.53,55,124,142 Studies using myeloid promoters have in general shown weak transactivations, on the order of twofold to fivefold.116,117 Recently, using multimerized reporter constructs, the transactivation domain of PU.1 was identified in the amino terminus.131 These studies defined multiple relatively weak transactivation domains; whether this indicates that each interacts with different proteins (see below) remains to be determined.

PU.1, like other Ets proteins, interacts with other transcriptional regulators. In B cells, PU.1 recruits a second, B-cell –specific DNA binding factor, NF-EM5 or Pip, to a site important for Ig κ 3′ enhancer function.143-146 For this interaction, phosphorylation of a serine residue at position 148 is necessary.144 However, such interactions have not been shown previously to play a functional role in previously described myeloid targets of PU.1, such as CD11b and the M-CSF receptor, and mutation of Ser148 does not affect the ability of PU.1 to activate these myeloid promoters.116 117 

As noted above, PU.1 can interact with TBP in vitro.57,132 An attractive hypothesis is that PU.1 may recruit the basal transcription machinery to myeloid promoters, which in general lack TATAA boxes, but the functional significance of this interaction is not known at this time. Similarly, these same studies showed that PU.1 can interact physically with RB. It has been shown that hypophosphorylated RB can negatively regulate the activity of another Ets factor, Elf-1, in the course of T-cell activation.147 Because RB becomes hypophosphorylated during myeloid differentiation,148,149 it possibly could regulate PU.1 function in these cells. Experiments to date have failed to show an effect of RB on PU.1 function on myeloid promoters,83 although it has been shown that RB can repress PU.1 function on an artificial promoter.132 A recent study using a protein interaction screen has identified a number of proteins that can bind to PU.1, although the functional consequences of these interactions remains to be determined.142 One of these is HMG(I)Y, which has been shown to augment the ability of the Ets factor Elf-1 to activate the IL-2 receptor β chain.150 To date, similar experiments with HMG(I)Y have failed to show binding to myeloid targets such as the M-CSF receptor or GM-CSF receptor α promoters or to augment the ability of PU.1 to activate these promoters. Another factor cloned in this study and shown to bind to PU.1 is NF-IL6β (same as C/EBPδ); in this case, it was shown that PU.1 and C/EBPδ could cooperatively activate an artificial reporter plasmid. These findings are interesting because they suggest that PU.1 might also interact with C/EBPα (see below). Similarly, in another study, PU.1 has been shown to interact with another basic leucine zipper (BZIP) transcription factor, c-Jun.151 Finally, PU.1 has been shown to functionally interfere with steroid hormone gene activation, and steroid hormone receptors can inhibit PU.1 transactivation function.152 Of particular relevance to myeloid development is the fact that these interfering effects were seen with the retinoic acid receptor.152 However, the functional significance with respect to myeloid development of all of these interactions is not known.

Ets family members have been shown to play an important role in several signal transduction pathways.153-156 PU.1 is phosphorylated in vitro by casein kinase II and JNK kinase, but not by ERK1 (MAP) kinase.157 A recent study has shown that lipopolysaccharide (LPS) can activate casein kinase II and phosphorylation of PU.1 in LPS-stimulated macrophage lines.158 The LPS stimulation of PU.1 transactivation of a reporter construct was abolished by a serine to alanine mutation of residue 148, suggesting that stimulation of macrophages with LPS leads to increased phosphorylation and activity of PU.1. The same PU.1 phosphorylation site has been shown to be important for B-cell gene activation (see above). A recent study implicated PU.1 in M-CSF–induced proliferation of murine macrophages, and this effect was abrogated by mutating two potential phosphorylation sites (Ser41 and Ser45) in the transactivation domain of PU.1 that are distinct from the postulated site of LPS stimulation at Ser148.159 Finally, a recent study suggested that there may be differences in PU.1 phosphorylation between myeloid cells and B cells, but not during myeloid commitment of multipotential progenitors.160 

A number of studies have addressed PU.1 function in myeloid cells by inhibiting its function. Addition of competitor oligonucleotides to human CD34+ cells specifically blocked myeloid CFU formation.44 The inhibition was only observed if the competitors were added very early during GM-CSF–induced myeloid maturation, before the upregulation of PU.1 expression. Several groups have addressed the function of PU.1 on murine development using targeted disruption of the PU.1 gene.26,161 One group reported that PU.1 −/− embryos died in utero, usually at day E16.26 These animals demonstrated a variable anemia, but no production of any type of white blood cells, including monocytes, neutrophils, and B cells, as might be expected based on the expression of PU.1 and its known target genes. The concomitant failure to produce T cells in the −/− animals was surprising, given that PU.1 has not been known to be expressed in this lineage (see above). These studies suggested that the defect was either due to a block of a very early multilineage progenitor cell or that T-cell development is dependent on the presence of macrophages and/or B cells.26 

A second PU.1 knockout animal yielded a phenotype with some distinct differences.161 The PU.1 −/− animals in this case were viable at birth and could be kept alive for days by housing them in a sterile environment with the administration of antibiotics. These animals also lacked monocytes and mature B cells, but were capable of producing B-cell progenitors. Several days after birth, T cells and cells resembling neutrophils in the peripheral blood were detected. In this case, the findings suggested a role for PU.1 in B-cell and monocytic development, which is more in keeping with its known pattern of expression and its known gene targets. Although neutrophilic cells were observed, they were Mac-1–negative and reduced in number, suggesting that targeting PU.1 results in a partial defect in neutrophil development. The reason for these marked differences between the two knockout phenotypes is not known at this time, but will be important to determine in that the former knockout model suggests that PU.1 plays an important role in multipotential cells,26 whereas the latter suggest a more limited role in B-cell and myeloid development.161 In vitro differentiation of PU.1 −/− ES cells does not produce macrophages and points to the M-CSF receptor as a major target for PU.1 in understanding its effect on myeloid differentiation.162 163 

Consistent with the finding that PU.1 has a major role in myeloid development has been the identification in the past three years of multiple myeloid genes regulated by PU.1 (Table 2). In transfection studies, PU.1 regulates a number of genes that appear as late markers of myeloid cells (Table 2). In addition, PU.1 sites are critical for the activity of a number of myeloid CSF receptor promoters, including the M-CSF receptor,117,164 the GM-CSF receptor α,54 and the G-CSF receptor promoter.53 Quantitative studies will be needed to establish whether hematopoietic cells in PU.1 knockout animals have decreased or absent expression of these three myeloid CSF receptors. If so, the role of expression of these receptors in myeloid development can be tested by restoring their expression singly or in combination in these PU.1 −/− animals. As noted above, studies in PU.1 −/− ES cells have confirmed that CD11b and the M-CSF receptor are major targets for PU.1.162,163 In addition to transactivating the promoters of the genes cited above, it is possible that PU.1 has other mechanisms of action. Recently, it was noted that PU.1 (but not Spi-B or other Ets factors) can bind RNA, suggesting that it could possibly play a role in posttranscriptional regulation.165 The biologic significance of these observations remains to be determined.

Although PU.1 was first isolated as a gene activated in murine erythroleukemia,37 so far it has not been implicated in the pathogenesis of human leukemias. The PU.1 gene has been mapped to 11p11.22, not a frequent site of chromosomal translocations found in human leukemia. PU.1 expression in leukemic myeloid lines is not higher than that observed in primary myeloid cells,95 and a recent survey of primary human leukemias found no significant discordance between PU.1 expression in leukemic samples and that predicted by the apparent differentiation stage of the leukemic cells (M.T. Voso, unpublished observations). However, no studies to date have addressed whether PU.1 is mutated in human leukemias.

Other Ets factors and myeloid development.Spi-B was isolated by hybridization with a PU.1 cDNA probe and, together with PU.1, forms a distinct subfamily within the Ets factors.130 In contrast to other Ets proteins,44 Spi-B can bind to many of the targets for PU.1 and can transactivate many of these myeloid genes.55,95 However, the observation that PU.1 knockout mice failed to produce certain myeloid lineages suggested that Spi-B might be expressed quite differently from PU.1. This was confirmed by studies showing that Spi-B is not expressed at significant levels in myeloid cells, suggesting that its role in myeloid differentiation and function is likely to be limited.55,95 Recently, it has been shown that the binding specificity of Spi-B is very similar but not identical to that of PU.1,118,166 and perhaps this can also contribute to the differences in function of these two factors. In addition, Spi-B and PU.1 are phosphorylated by different kinases.157 

To date the role of other Ets factors in myeloid development has not been well defined. A number of other Ets factors are expressed in myeloid cells, including Ets-2, Fli-1, and Elf-1167,168 (D.E.Z. and D.G.T, unpublished observations). Ets-2 is capable of transactivating the murine M-CSF receptor promoter,169 but targeted disruption of the Ets-2 gene did not affect the ability of ES cells to form macrophages in vitro,163 suggesting that Ets-2 does not play a necessary role in myeloid development. Ets-2 may play an important role in activation or signaling in macrophages.107,156,164 The ubiquitous Ets protein GABP is important for the activity of the CD18 protein and can functionally cooperate with PU.1.170 GABP from myeloid cells can also bind to the neutrophil elastase promoter and cooperates with c-myb and C/EBP to transactivate this promoter in nonmyeloid cells (A. Rosmarin, unpublished observations). Recently, another ubiquitously expressed Ets protein, TEL, was isolated from a patient with chronic myelomonocytic leukemia as a fusion protein with the platelet-derived growth factor (PDGF) receptor.171 TEL can also form a fusion protein with AML1 in a large percentage of cases of pre-B–cell acute lymphoblastic leukemia (ALL).172 At this time, the precise role of TEL in myeloid development and in the pathogenesis of myeloid leukemia is not known.173 

C/EBP (CCAAT/enhancer binding protein; now known as C/EBPα) was isolated as a rat liver protein that bound to viral enhancer sequences174,175 and is a member of one of several leucine zipper transcription factor families, including the fos/Jun family and the ATF/CREB family.176-178 C/EBPα binds as a homodimer or heterodimer with other C/EBP proteins or other transcription factors and has been shown to regulate a number of hepatic and adipocyte genes. C/EBPα is upregulated and plays an important role in adipocyte differentiation and in this cell type functions in fully differentiated, nonproliferative cells; inhibition of C/EBPα blocks differentiation; and expression of C/EBPα induces differentiation.179,180 Indeed, several studies have indicated that C/EBPα can act as a general inhibitor of cell proliferation and in this respect resembles a tumor suppressor.181-183 C/EBPα is part of a family of leucine zipper transcription factors, including C/EBPβ and C/EBPδ, that heterodimerize and are differentially regulated during adipocyte differentiation.179,184,185 Another very interesting C/EBP gene, C/EBPε, was very recently isolated and shown to be preferentially expressed in myeloid cells.186,187 Both C/EBPα and C/EBPβ have single mRNAs that can encode transcriptionally active and repressive forms, depending on the usage of alternative start AUG codons in the same reading frame.188,189 In addition, another C/EBP family member, CHOP-10, can dimerize with C/EBP proteins to inhibit transcriptional activation and is found at a translocation breakpoint in liposarcomas.190,191 Of note is that CHOP can specifically block C/EBPα activity and induce increased apoptosis of myeloid 32D cells.191 

In murine adipocyte cell lines, C/EBPα is transcriptionally upregulated (and C/EBPβ is downregulated) with adipocyte differentiation and binds to its own promoter.192 In addition, c-myc overexpression can block differentiation of adipocytes, possibly by repressing the C/EBPα promoter.193 Interestingly, although both murine and human C/EBPα promoters are autoregulated, the mechanisms of autoregulation are different. The murine C/EBPα promoter has a binding site for C/EBPα.192 The human C/EBPα promoter does not conserve the C/EBPα binding site found in the murine promoter, and the autoregulation is indirect and mediated by the action of C/EBPα on a helix-loop-helix protein, upstream stimulatory factor (USF).194 Studies of C/EBPα promoter analysis in myeloid cells have not been reported.

Whereas the C/EBP proteins are expressed in a number of different tissues, their expression in the hematopoietic system may be limited to myeloid cells. It has shown that C/EBPα is specifically expressed in human myelomonocytic cell lines and not in human erythroid, B-cell, and T-cell lines,195 consistent with the myeloid-specific expression previously noted for avian C/EBP.196-199 In studies of murine 32D cells and human leukemic lines, such as HL-60 and U937 cells, the C/EBP proteins showed a pattern of expression quite different from that observed in adipocytes.195,200 In these studies, C/EBPα was observed to be highly expressed in proliferating myelomonocytic cells upon induction of differentiation and downregulated with maturation, whereas C/EBPβ and C/EBPδ were upregulated. However, recent Northern blot analysis of human primary CD34+ cells shows that C/EBPα expression is maintained during granulocytic differentiation but is markedly downregulated with monocytic or erythroid differentiation. In addition, Northern blot analysis of mature peripheral blood neutrophils shows very high levels of C/EBPα mRNA, which was completely undetectable in adherent peripheral blood monocytes (H. Radomska and D.G.T., manuscript submitted). In addition, C/EBPα was noted to be upregulated as single CD34+/CD38 cells were differentiated into granulocytic colonies; no such upregulation was observed during colony-forming unit-macrophage (CFU-M) colony formation.134 These studies point to a role of C/EBPα in neutrophilic but not monocytic lineage development.

As noted above, C/EBPα was the first protein noted to have the leucine zipper motif.176,201 The leucine zipper consists of repetitive leucine residues spaced every 7 amino acids that results in an α helical amphipathic structure with hydrophobic and hydrophilic faces on each side of the helix. Just amino terminal to the zipper is a basic region that is highly positively charged and directly interacts with DNA. The leucine zipper is directly involved in homodimerization and heterodimerization. C/EBPα, C/EBPβ, and C/EBPδ are strongly similar in their C terminal basic region and leucine zipper domains and diverge in the N-terminal transactivation domain.61,179,184,202,203 Adding to the complexity, other DNA binding proteins, including CTF/NF-1204 and NF-Y (also known as CBF and CP1),205-207 can bind to CAAT containing sequences. C/EBP binding sites consist of two half sites, but even the sequence CCAAT was not always required for binding. Despite the high degree of similarity of the carboxyl terminal basic-zipper DNA binding domain, C/EBPα and C/EBPβ can bind with vastly different affinities to the same promoter site.208 The consensus binding site for C/EBPα has been recently determined using PCR binding site selection.209 

In addition to other members of the C/EBP family, the C/EBP proteins can interact with a number of transcription factors, including NF-κB and Rel proteins,210,211 members of the CREB/ATF family,98,178 Sp1,212 RB,213 and members of the fos/jun zipper family.214 The amino terminal region of C/EBPα has been shown to physically interact with TBP.61 As noted above, C/EBPδ has been shown to interact with PU.1,142 and PU.1 can physically interact with C/EBPα83 and C/EBPβ as well (P. Auron, unpublished observations). As noted above, C/EBPα and C/EBPβ are most similar in their carboxyl terminal basic-zipper DNA binding domain and less so in the amino terminus, perhaps explaining why they can also show very different abilities to interact with other proteins.212 Another functionally important interaction of relevance to myeloid gene regulation is that between C/EBPα and AML1, which is important for M-CSF receptor promoter function in transfection studies (see below).215 Recently, it has been shown that the underphosphorylated form of the retinoblastoma (RB) protein can interact physically with C/EBP proteins to increase DNA binding and transactivation of target genes during adipocyte differentiation.216 As RB becomes underphosphorylated with myeloid differentiation,148 149 it could positively regulate C/EBPα-induced granulocytic maturation.

Recently, lines of mice harboring a knockout of the C/EBPα gene were generated.217,218 Heterozygous mice are outwardly normal, but homozygous mice die within the first few hours after birth of impaired glucose metabolism; their viability can be extended to about 1 day with injections of glucose. The mice are unable to properly synthesize and mobilize glycogen and fat. Analysis of the hematopoietic system in embryonic and newborn mice has demonstrated a significant defect in production of granulocytic cells.28 Newborn knockout (−/−) animals do not produce any mature neutrophils, which comprise 90% of the peripheral blood white blood cells of newborn heterozygote (+/−) or wild-type (+/+) mice. Cells that appear to be immature myeloid cells are observed in the peripheral blood. These cells stain with Sudan black, a characteristic of myeloid cells, and have increased myeloid CFU potential compared with those from heterozygote blood. Interestingly, many cells in the CFU from the knockout blood are immature in morphology as well, similar to what is observed in CFU from leukemic cells. Eosinophils are also not observed, but all of the other lineages, including peripheral blood monocytes and peritoneal macrophages, red blood cells, platelets, and lymphoid cells, appear quantitatively unaffected. Fluorescence-activated cell sorting (FACS) analysis in embryonic and newborn animals confirmed that myeloid markers (Mac-1 and Gr-1) were greatly reduced, with normal B- and T-cell subsets. Expression of the G-CSF receptor mRNA was profoundly and selectively reduced, whereas that of M-CSF receptor and GM-CSF receptor α, βc, and βIL3 were all comparable to wild-type. Interestingly, a fourfold increase in mRNA for Epo receptor was detected, although whether this is due to a negative effect of C/EBPα on Epo receptor expression in precursor cells or alternatively a reflection of an increased number of erythroid cells in C/EBPα −/− livers has not been determined. Compared with wild-type animals, maturation of immature myeloid cells in vivo in response to G-CSF was not observed, as assessed by both morphology and FACS analysis of Gr-1 expression. In addition, no colony-forming units-granulocyte (CFU-G) could be obtained using C/EBPα −/− newborn liver, although other types of colonies (colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM], colony-forming unit-erythroid [CFU-E], colony-forming unit–granulocyte-macrophage [CFU-GM], and colony-forming unit-macrophage [CFU-M]) were quantitatively equal to wild-type animals. These findings suggested that much of the phenotype may be due to decreased or absent G-CSF signaling due to markedly reduced receptor levels. However, G-CSF receptor knockout animals produce mature granulocytes, in contrast to C/EBPα knockouts, strongly suggesting that there must be important C/EBPα target genes in myeloid progenitors in addition to the G-CSF receptor.219 Transplantation of C/EBPα fetal liver into sublethally irradiated animals resulted in detection of T cells but not myeloid cells of donor origin, showing that the defect is indeed in the hematopoietic cells.28 

A number of studies have pointed to the role of C/EBPβ in myeloid cells. The avian homolog of C/EBPβ (NF-M) is a myeloid-specific factor that activates the promoter for cMGF, which is related to G-CSF and IL-6.196-199 In mammalian cells, C/EBPβ has been described as having low activity until activated by LPS, IL-1, IL-6, and other inflammatory mediators, which induce its translocation to the nucleus, where it can activate cytokine genes such as IL-6 and G-CSF.185,220 Changes in C/EBPβ phosphorylation (but not in C/EBPα) have also been described during myeloid differentiation of a progenitor cell line.160 Human C/EBPβ is also known as NF-IL6.185 C/EBPβ can also be activated in other cell types by phosphorylation without translocation.221 In one report, targeted disruption of C/EBPβ leads to defects in killing of Listeria and tumor cells by macrophages.222 In a second study, disruption of C/EBPβ led to an increase in IL-6 production (previously it was thought that C/EBPβ, or NF-IL6, was essential for IL-6 production) and hyperproliferation of a number of different hematopoietic lineages, a syndrome resembling Castleman's disease.223 Knockout animals from both of these studies can get this syndrome as the animals get older, but it is not seen in young mice kept in a sterile environment.224 In these younger mice, in the absence of inflammation, myelopoiesis was apparently not adversely affected, consistent with a role of C/EBPβ in cytokine activation rather than lineage development.

As noted above, C/EBPβ (NF-IL6) regulates a number of cytokine genes and may contribute to normal myeloid development as well as activation of mature myeloid cells in response to an inflammatory stimulus. In particular, targeting of C/EBPβ resulted in a reduction of G-CSF production in macrophages but not other cell types.222 C/EBPα has been noted to regulate the promoters for several myeloid granule proteins, including myeloperoxidase and neutrophil elastase.87,88,160 In addition, C/EBP sites, like PU.1 sites, are critical for the activity of a number of myeloid CSF receptor promoters, including the M-CSF receptor,117 the GM-CSF receptor α,54 and the G-CSF receptor promoter.53 In the C/EBPα knockout mice, G-CSF receptor mRNA was selectively and significantly reduced.28 Interestingly, no reduction was noted in the levels of M-CSF receptor and GM-CSF receptor (α and β chain) mRNA, suggesting that perhaps other factors (such as C/EBPβ) can compensate for C/EBPα in some but not all instances.

With respect to the possible role of C/EBP proteins in leukemia, the C/EBP proteins have not been implicated as transforming proteins, with the exception of CHOP10.190,225 Indeed, C/EBPα has been shown to inhibit cell proliferation in fibrosarcoma lines through the cyclin-dependent kinase inhibitor p21183 and can act as a tumor suppressor of hepatoma lines and other cell types.181,182 The human C/EBPα gene maps to chromosome 19q13.1 and C/EBPβ maps to 20q13.1.226 Neither of these is a frequent site of chromosomal translocations found in human myeloid leukemia. Studies of C/EBP expression in primary human leukemias have not been reported. However, given the phenotype of the C/EBPα knockout mouse, in which there appears to be a block in granulocyte maturation, it will be of interest to look for abnormalities of C/EBP expression or mutations in myeloid leukemias, which also represent states with a block in maturation.

In summary, the C/EBP proteins are differentially expressed and can form many interactions with themselves and other transcription factors. These studies show that C/EBPβ (and C/EBPδ) may be involved in activation of cytokines in mature cells, whereas C/EBPα has a major role in granulocytic maturation through regulation of the G-CSF receptor and other as yet not identified target genes.

Other factors binding to CCAAT sites and myeloid development.In addition to the C/EBP proteins, the CCAAT displacement protein (CDP) has also been implicated in myeloid development. This protein was observed to negatively regulate genes by binding to a CCAAT box and displacing the binding of positively acting factors.227 It was subsequently shown to be capable of binding to the gp91phox promoter and repressing this cytochrome component gene expressed specifically in myeloid cells.228,229 At this time no characterization of the positively acting factors that are presumed to be displaced at this site has been made. CDP is expressed at highest levels in undifferentiated myeloid cell lines and is downregulated with differentiation, providing a mechanism for the upregulation of gp91phox observed with myeloid maturation. Importantly, this is one of the few examples explaining the potential mechanism of upregulation of myeloid targets with myeloid differentiation. In most other cases, the mechanism of upregulation is largely unknown. Recently, it has been shown that CDP can also repress the lactoferrin promoter.230 In these studies, overexpression of CDP in myeloid stem cells blocked lactoferrin expression after G-CSF–induced neutrophil maturation without blocking phenotypic maturation. Furthermore, these investigators observed coordinate repression of multiple secondary granule protein genes, including lactoferrin, neutrophil collagenase, and neutrophil gelatinase, suggesting that CDP repression is a common mode of regulation of this class of myeloid promoters (N. Berliner, unpublished observations). Other factors might also act in a similar manner to repress positive activators during differentiation. For example, a factor that is downregulated during adipocyte differentiation and inhibits C/EBPα function, presumably through its similarity to carboxypeptidase, has recently been described,231 but it is not known if it inhibits C/EBPα in hematopoietic cells.

An example of a transcription factor that plays an important role in normal monocytic gene expression and in acute myelogenous leukemia is AML1. AML1 is a member of the core binding factor (CBF) or polyoma enhancer binding protein 2 (PEBP2) family of transcription factors. The CBF factors consist of heterodimers between DNA binding α subunits and a β subunit (CBFβ) that does not bind DNA directly but that enhances the binding of the α subunit.232,233 Multiple α subunit genes, including CBFA1, AML1 (CBFA2), and CBFA3, have been detected,233-237 although the role of these other AML1 family members in myeloid development and leukemia is not clear. In addition, alternatively spliced isoforms of the α and β subunits have been detected. In particular, a short form and two long forms of AML1 have been described, and it is the long form that appears to include the transactivation function.235-238 All of the CBFα proteins contain a runt domain, which is similar to the Drosophila pair-rule gene, runt, an early acting segmentation protein that regulates the expression of other segmentation genes.239,240 This runt homology domain (rhd) confers the ability of AML1 to bind to its consensus sequence, TGT/cGGT, and the ability of AML1 to interact with its cofactor CBFβ, which enhances the DNA binding ability.232,233 241 

AML1, normally expressed in hematopoietic tissues and during myeloid differentiation,134,237,242 is also expressed in nervous tissue, skeletal muscle, and reproductive tissues as well.243 Knockout studies of AML1 have determined that AML1 is necessary for normal development of all hematopoietic lineages,49,50 and similar effects have been observed with targeted disruption of the CBFβ subunit.244 In these studies, primitive hematopoiesis was apparently normal, but severe impairment of definitive hematopoiesis was observed both in the animals and during in vitro differentiation of −/− ES cells, with defects observed in all lineages examined.

AML1 may act to facilitate the action of other adjacent transcription factors. The AML1 site in the M-CSF receptor promoter is located between the C/EBPα and PU.1 sites, two transcription factors that are important for myeloid gene expression.52,215,245 Significantly, although the C/EBP site is critical for M-CSF receptor activity in transfection experiments,52 C/EBP alone does not transactivate M-CSF receptor promoter activity. The adjacent factor AML1, along with CBFβ, can by itself activate the M-CSF receptor promoter sixfold, but the synergistic activation by C/EBP added to AML1 and CBFβ is much greater (>60-fold). All C/EBP proteins share a highly similar bZIP domain,179,184 and AML1 interacts with the bZIP fragment of C/EBP, explaining why C/EBPα, C/EBPβ, and C/EBPδ can all synergistically activate the M-CSF receptor promoter with AML1. The physical interaction between C/EBP and AML1 could either stabilize binding of both to the M-CSF receptor, or their interaction might provide a surface for another transcription factor to bind and activate the M-CSF receptor promoter. Other examples of interactions of AML1 and other transcription factors include synergism with Ets-1 and c-myb to activate T-cell receptor enhancers.246-249 Because Ets factors, such as PU.1, and c-myb both play an important role in myeloid development, it is likely that these interactions with AML1 will be important in myeloid gene expression as well.

AML1 can be phosphorylated at two serine residues within a proline-, serine-, and threonine-rich region in its carboxyl terminal domain after activation of the extracellular signal regulated kinase (ERK1).250 These serine residues are critical for AML1-dependent transformation of fibroblast cell lines and ERK1-dependent transactivation of a T-cell receptor enhancer target gene. IL-3 treatment of the hematopoietic cell line BaF3 results in phosphorylation of AML1, suggesting that this signalling pathway may play an important role during hematopoietic development.

Role of AML1 in leukemogenesis.AML1 was identified by studying one of the most frequent chromosomal translocation found in AML, t(8; 21)(q22; q22).17,39,241,251,252 AML1 fusion proteins are also involved in other forms of leukemia, including t(3; 21) therapy-related acute myeloid leukemia/myelodysplasia or chronic myelogenous leukemia in blast crisis (AML1/MDS1, AML1/EAP, and AML1/Evi-1) and also the t(12; 21) in childhood B-cell acute lymphoblastic leukemias (TEL/AML1).17,172,251,253-256 The β subunit of CBF, CBFβ, is also involved in a chromosomal inversion, inv(16)(p13; q22), associated with French-American-British (FAB) M4eo AML.257 Therefore, each of the two chains of the CBF heterodimer is directly implicated in the pathogenesis of AML.

As noted above, AML1 is involved in the (8; 21) translocation, associated with the FAB M2 form of AML, which results in the production of the AML1/ETO fusion protein. The mechanism by which AML1/ETO accomplishes leukemic transformation is unknown. In this case, the 5′ part of the AML1 gene, including the amino terminal DNA binding runt domain but lacking the carboxyl terminal activation domain, is fused to almost the entire ETO gene on chromosome 8. Recent studies have indicated that this AML1/ETO fusion protein can act as a dominant negative inhibitor of AML1 transactivation of such AML1 targets as the T-cell receptor β (TCRβ) enhancer.236,238,258 It has recently been reported that the t(12; 21) fusion protein, TEL/AML1, also causes the same interference with AML1 transactivation of the TCRβ enhancer.259 Therefore, the expression of some of the normal AML1 gene targets that play a key role in monocytic differentiation might be adversely affected by AML1/ETO, and these include GM-CSF,236,258 IL-3,260,261 M-CSF receptor,52 and myeloperoxidase and neutrophil elastase.87 262 

Recently, it was shown that AML1/ETO and AML1 work synergistically to transactivate the M-CSF receptor promoter, thus exhibiting a different activity than previously described.263 This indicates that AML1/ETO not only can repress, but also can enhance AML1 transactivation of its target genes. Endogenous M-CSF receptor expression was examined in Kasumi-1 cells, derived from a patient with AML-M2 t(8; 21) and the promonocytic cell line, U937. Kasumi-1 cells exhibited a significantly higher level of M-CSF receptor expression than U937 cells. Bone marrow from patients with AML-M2 t(8; 21) also exhibited a higher level of expression of M-CSF receptor compared with normal controls.263 Signaling through the M-CSF receptor promotes cell proliferation by inducing the G1/S transition because of the effect on cyclins D and E.264,265 This effect on proliferation can be tied to the oncogenic nature of the M-CSF receptor, which was first discovered as the cellular counterpart to the transforming oncogene, v-fms.266 Overexpression of the M-CSF receptor causes transformation of NIH3T3 cells and in mice leads to a myeloblastic leukemia.267 268 A premature upregulation of M-CSF receptor expression by AML1/ETO could be one of the factors contributing to leukemogenesis AML.

To study how the fusion protein produced by the t(8:21) translocation leads to the development of myeloid leukemia, knock-in mice have been generated that express the AML1-ETO fusion protein. Mice heterozygous for the AML1-ETO allele die in midgestation with hemorrhaging in the central and peripheral nervous system and exhibit a severe block in fetal liver hematopoiesis.269 This phenotype is very similar to that resulting from homozygous disruption of the cbfα2 (AML1) and cbfβ genes.49,50,244 However, significant differences between AML1-ETO knock-in and cbfα2 −/− or cbfβ −/− mice were observed in hematopoietic CFU assays. Yolk sac from AML1-ETO knock-in mice generated solely homogenous macrophage colonies. The total number of macrophage colonies is similar to the sum of all type of colonies from yolk sacs of wild-type mice. In contrast, no colonies from cbfα2 −/− or cbfβ −/− mice could be detected. These results, like those noted above in which the AML1-ETO fusion protein activates the M-CSF receptor promoter, indicate that the AML1-ETO fusion protein affects hematopoiesis in a manner that is not simply a block of wild-type AML1 function, and these effects could be important in leukemogenesis. Mice heterozygous for a knock-in of the cbfβ-myh11 allele, which mimics the inv(16)(p13; q22) associated with AML-M4Eo form of AML, also die in midgestation from the same pattern of central nervous system hemorrhaging and impairment of fetal liver hematopoiesis. However, instead of preferential macrophage differentiation from early progenitor cells, these embryos exhibit a significant delay in maturation of yolk sac-derived primitive erythrocytes.270 Although t(8:21) and inv(16) disrupt genes encoding different subunits of a single transcription factor complex, the fusion genes have different effects on hematopoiesis, consistent with their association with distinct AML subtypes.

Several lines of evidence indicate a key role for the retinoic acid receptor (RAR) in myeloid differentiation. Vitamin A deficiency is associated with defective hematopoiesis,271 and retinoids stimulate granulopoiesis.272,273 Retinoic acid (RA) can induce differentiation of the HL-60 cell line274 and of primary leukemic cells.275 There are three genes encoding RARs; RARα, RARβ, and RARγ (reviewed previously276-278 ). RARα is preferentially expressed in myeloid tissue.279-281 RARα binds to retinoic acid response elements consisting of a direct repeat (A/G)G(G/T)TCA separated by 2 or 5 nucleotides as a heterodimer with the retinoid X receptor RXR282-284 and stimulates transcription in response to all-trans retinoic acid (ATRA).285 RARα was mutated in a retinoid-resistant HL-60 cell line with this deficit corrected by re-expression of wild-type receptor.286-288 Furthermore, introduction of a dominant negative form of RARα into a multipotent hematopoietic cell line changed the fate of these cells from the granulocyte/monocyte lineage to the mast cell line.289 In addition, GM-CSF–mediated myeloid differentiation of these cells was blocked at the promyelocyte stage.45 This basic information was complimented by clinical data indicating that patients with APL could be induced into complete remission with ATRA (reviewed previously19,290 ). It was found that APL associated with t(15:17) disrupted the RARα linking it to the PML gene, yielding the fusion protein PML-RARα.291-296 PML-RARα is an aberrant retinoid receptor with altered DNA binding and transcriptional activities.292,294,296-298 PML-RARα can block the effect of wild-type retinoic acid receptor on many promoters in a dominant negative manner. Two other APL-associated rearrangements of the RARα gene were identified: translocation (11; 17)40,299 fusing the PLZF gene to RARα and t(5; 17)300 linking the nucleophosmin (NPM) gene to RARα. All three situations yield similar chimeric RARα proteins, yet only t(15; 17) patients clearly respond to ATRA therapy.301,302 Expression of the PML-RARα fusion protein in myeloid cells inhibits differentiation in the presence of low levels of ATRA303,304 and actually accelerates differentiation in the presence of pharmacologic doses of RA.304 Expression of PML-RARα in transgenic mice impairs myelopoiesis,113 and work from another group indicated that PML-RARα could induce altered myeloid development, including increased immature and mature myeloid cells, as well as a leukemic syndrome that is ATRA responsive.115 Another group has recently described similar results in PML-RARα transgenic animals using another promoter.109 Together, the experimental and clinical data indicate that RARα function is required to fully proceed through myeloid differentiation. Disruption of RARα function likely selects for the promyelocyte phenotype. However, the nature of the fusion partner and its molecular mechanisms of action apparently play a role in the ability of the leukemic cells to differentiate in response to ATRA.

ATRA treatment drives the expression of multiple myeloid genes, including those for cell surface adhesion molecules, intrinsic host defense systems, extrinsic cytokines, colony-stimulating factor receptors, structural proteins, and enzymes. Some of these are induced with some delay after ATRA treatment, making them unlikely primary targets of RARα. The few identified direct targets of RARα tend to themselves be transcription factors, including the RARs themselves.284 ATRA treatment of fresh APL cells upregulates RARα, correlating with the presence of a RARE in RARα promoter.305,306 Therefore, one way that ATRA may induce myeloid differentiation may be to upregulate the RARα gene, overcoming the dominant negative PML-RARα protein. A recently identified direct target of RAR in myeloid cells is the cyclin-dependent kinase inhibitor p21.307 Another tantalizing set of targets for RARα in myeloid differentiation includes hox family of homeobox-containing transcription factors, which are expressed in myeloid cell lines in a coordinated, dynamic manner.32,33,308-313 In embryonic carcinoma cells homozygous for a targeted disruption in the RARα gene, ATRA treatment fails to induce the hoxb1 and CRABPII expression, indicating that these are true direct targets of RARα.284,314 Identification of further direct target genes of RARα during myeloid differentiation will require use of techniques such as differential screening315 or differential display316 of myeloid cells treated for brief periods with ATRA.

Finally, although the RARα locus and all of the other nuclear receptors have been disrupted by gene targeting in mice (reviewed previously317 ), no major defects in hematopoiesis were described in these animals.318-320 This may reflect the ability of the receptors to compensate for each other in a redundant manner. This is analogous to the way alternative forms of the RAR could rescue mutated HL-60 cells with a RARα mutation.288 Multiple matings of animals deficient in the various RAR, RXR, and other nonsteroid nuclear receptors may yield further insights as to the exact requirements for this class of transcription factor in hematopoiesis.

Transcription factors belonging to the zinc finger family are among the most numerous in vertebrate organisms. These proteins contain cysteine and histidine residues that coordinately bind zinc ions to form a protein loop capable of specifically interacting with DNA.321 The Drosophila Krüppel-related zinc finger proteins are distinct from other Cys/His finger proteins because they contain a relatively invariant amino acid sequence linking the zinc fingers of the form HTGEKP(F/Y)XC. This H/C link is present in a number of zinc finger transcription factor proteins of higher eukaryotes, including Sp1,322 the EGR family of transcriptional activators,323 and the WT-1 tumor suppressor protein.324,325 Myeloid-specific zinc finger proteins were identified by their similarity to the Krüppel sequence (MZF-1),30 by subtraction cloning from myeloid cells (Egr-1),25 by their involvement in chromosomal translocation involved in APL (PLZF),299,302 and by their involvement in apoptosis associated with myeloid differentiation (Requiem).326 In addition, a zinc finger gene not normally expressed in myeloid cells was isolated by its activation in murine models of leukemia by retroviral insertion (Evi-1)327 and has subsequently shown to be involved in human leukemia when fused to the AML1 gene.17,328 329 Interestingly, relatively few of these proteins were identified by traditional promoter analysis, with the notable exception of Sp1. On the contrary, these zinc finger proteins are in general factors in search of molecular targets and mechanisms in myeloid differentiation.

The PLZF gene.The promyelocytic leukemia zinc finger (PLZF) gene, potentially important for myeloid development, was identified by its rearrangement in APL with a variant translocation t(11; 17) (q23; q21).40,299,330 The t(11; 17) APL patients were generally resistant to both chemotherapy and differentiation therapy with ATRA,302 suggesting that the nature of the fusion partner with RARα may determine the clinical course of APL. PLZF on chromosome 11 encodes a zinc finger transcription factor,299 whereas the partner protein with RARα in t(15; 17) APL is PML, a RING finger protein of unknown function (reviewed previously19 ). The t(11; 17) fusion yields two reciprocal transcripts expressed in all patients tested: PLZF-RARα, predicted to encode an aberrant retinoid receptor, and RARα-PLZF, fusing the A-activation domain of RARα to the last 7 zinc finger motifs of PLZF.

In the hematopoietic system, PLZF is expressed in myeloid but not in lymphoid cell lines.299 Upon treatment of NB4 or HL-60 cells with retinoic acid, PLZF levels decline (Chen et al299 and A. Chen, S. Waxman, and J. Licht, unpublished data). The murine homologue of PLZF was found to be expressed at highest levels in multipotent progenitor cell lines such as FDCP-MixA4 and at lower levels in committed cell lines.331 When the multipotent FDCP-MixA4 cell line was induced to differentiate, PLZF levels decreased. Murine PLZF mRNA was also detectable in pro-B–cell lines but not in more mature B- or T-cell lines.331 PLZF was not expressed in undifferentiated embryonic stem cells but was upregulated as ES cells were induced to differentiate into embryoid bodies. In the developing mouse embryo, PLZF is expressed in the aorta, gonadal, and mesonephros region (AGM), a region thought to give rise to hematopoietic stem cells. Finally, CD34+ human progenitor cells could be immunostained with PLZF antisera in a distinct nuclear speckled pattern.331 Together, this information suggests that PLZF may be a marker of and a critical gene for the early hematopoietic stem cell. Downregulation of PLZF may be a necessary step for the committed division and differentiation that accompanies normal bone marrow maturation.

By immunoprecipitation of transfected cells, the PLZF protein was identified as an 81-kD nuclear species331,332 phosphorylated on serine and threonine but not tyrosine residues (R. Shaknovich and J. Licht, manuscript in preparation). A biphenotypic T-cell/macrophage line, presumably representing a primitive transformed cell, expressed high levels of PLZF mRNA and 81-kD PLZF protein when treated with the calcium ionophore A23187, correlating with the induction of a more monocytoid phenotype. Immunofluorescent confocal microscopy showed that PLZF was localized to approximately 50 small nuclear subdomains, whereas the PML protein of t(15; 17) APL was localized in approximately 5 to 10 larger nuclear structures (nuclear bodies or PODs333-335 ) and was present before and after A23187 treatment. It is uncertain if in other cell types these two APL-associated proteins might be localized to the same nuclear domains.

PLZF is a sequence-specific DNA binding protein recognizing a sequence with a core of TAAAT.336 This site was cloned upstream of a reporter gene and was found to mediate transcriptional repression by PLZF. At least one repression domain within PLZF maps to an evolutionarily conserved sequence known as the POZ (poxvirus-zinc finger) or BTB (broad complex-tramtrack-bric-a-brac) domain.337,338 This sequence also mediates self-association by PLZF and is required for the localization of PLZF into a speckled subnuclear pattern.332 339 Whether the domains that mediate homodimerization and transcriptional repression are identical is not known. The last 7 zinc fingers of PLZF that are retained in the RARα-PLZF fusion protein can bind to the same site as the 9 zinc fingers of PLZF, suggesting that the RARα-PLZF protein could act as a dominant negative protein binding and altering transcription of PLZF target genes.

The PLZF-RARα fusion protein has properties quite similar to the PML-RARα fusion protein of t(15; 17)-associated APL. Both fusion proteins can bind as homodimers to a retinoic acid response element (RARE).297,332,339 Homodimerization by PML is mediated by a coiled-coil motif,297 whereas in PLZF the POZ domain mediates self-association.339 In an electrophoretic mobility shift assay (EMSA) both PML-RARα and PLZF-RARα homodimers are chased into novel complexes of higher and lower electrophoretic mobility by addition of RXRα. This suggests that both fusion proteins may work in a similar manner, forming multimeric complexes in the cell that could act to sequester limiting amounts of RXRα, the essential cofactor for RARα function, in the cell. Both PML-RARα and PLZF-RARα can act in a dominant negative manner to inhibit the activity of wild-type RARα294,296,298 and other nuclear receptors such as the vitamin D3 receptor (J. Licht and M. English, unpublished data).297 This effect can be partially relieved by overexpression of RXRα, consistent with the notion that the aberrant receptors generated in APL block myeloid differentiation at least in part through limiting the ability of RARα to bind to its targets in combination with RXR. Dominant negative forms of RARα can block myeloid differentiation at the promyelocyte stage.45,289,340 This correlated with the clinical finding that RARα is rearranged in three translocations, t(15; 17), t(11; 17), and t(5; 17), all yielding APL.300 341 Thus, the block in ATRA-mediated signaling may help select the APL phenotype but may not necessarily determine whether the disease is ATRA-responsive. Further studies of the growth-inhibiting properties of PLZF suggest a reason why t(11; 17) APL may not respond to therapy.

Pools of murine myeloid 32DCL3 cells transduced with a retrovirus to overexpress the PLZF protein were significantly growth inhibited when grown in IL-3 or GM-CSF and retarded in the G1 phase of the cell cycle. In addition, the cells exhibited a higher rate of programmed cell death and a reduced ability to differentiate in response to G-CSF or GM-CSF.342 The high level of expression of PLZF in the hematopoietic precursor cell may play a role in the relative quiescence of these cells. Downregulation of PLZF during myeloid differentiation may be accompanied by cycles of committed cell division. In this way, PLZF does seem similar to PML,343-345 because both proteins can repress cell growth. However, t(11; 17) generates RARα-PLZF, a protein that can potentially interfere with the normal transcriptional functions of PLZF by binding to and dysregulating PLZF target genes. In contrast, the RAR-PML transcript is variably found in t(15; 17) APL19 and may not be able to affect the function of wild-type PML. Consistent with a central role for PLZF disruption in t(11; 17) APL phenotype, RARα-PLZF may confer accelerated growth to 32DCL3 cells. Hence, t(11; 17) may be a resistant disease due to the presence of two oncogenes working through different mechanisms, PLZF-RARα and RARα-PLZF. It remains to be determined what genes are targeted by PLZF and how these play a role in the growth and differentiation of myeloid tissue.

The myeloid zinc finger protein MZF-1.MZF-1 has multiple (13) zinc finger domains, divided in two groups.346 The amino-terminal group has 4 fingers, and the carboxyl-terminal group has 9 fingers. There are acidic regions in the amino-terminal nonzinc finger portion of the protein that may be part of the transcriptional regulatory domain. Interestingly, there is a 24 amino acid glycine-proline–rich link between the first and second zinc finger regions. Glycine-proline–rich domains have also been implicated in transcriptional regulation in a large number of transcription factors, including Oct-3, Rex-1, and CP-1.346 

By Northern analysis, MZF-1 was found to be specifically expressed in myeloid cell lines.346 By cRNA in situ hybridization of normal marrow, MZF-1 was found to be expressed in myeloid cells,347 from myeloblasts to metamyelocytes, but in no other marrow cell types, implying a role for MZF-1 in myeloid development. Using in situ chromosomal hybridization, MZF-1 was localized to human chromosome 19q13.4.346 It is the telomeric-most gene on 19q, with its promoter region being less than 10 kb from the telomeric repeats.348 The finding that MZF-1 is located at the telomere of chromosome 19q is significant because there is evidence that aging hematopoietic stem cells lose telomeric size with time.349 In addition, telomeres shorten with transformation of myelodysplasia to leukemia.350 With age, the incidence of stem cell disorders such as myelodysplasia and leukemia increases markedly. It is possible that the regulatory region of MZF-1 or the transcribed sequence is disrupted with age, which could play a role in the increased incidence of hematopoietic stem cell disorders.

The consensus DNA binding sites of MZF-1 were isolated by mobility shift selection of degenerate oligonucleotides and PCR amplification.351 The first finger domain, zinc fingers 1-4 (ZF1-4), bound to a consensus sequence of 5′-AGTGGGGA-3′, whereas zinc fingers 5-13 (ZF5-13) bound to a consensus of 5′-CGGGnGAGGGGGAA-3′. These guanine-rich sites resemble NF-κB binding sites. The full-length recombinant MZF-1 could bind to either sequence. Indeed, the two MZF-1 finger domains, ZF1-4 and ZF5-13, could bind to each other's consensus binding sequence. In addition, it was discovered that ZF5-13 probably needs all 9 fingers to bind to its consensus sequence. Deletion of as few as 3 fingers from either end of ZF5-13 abrogates DNA binding.351 

Computer searches of data bases for promoter sequences that contained these consensus MZF-1 binding sites found several possible matches. The promoters of the myeloid genes CD34, myeloperoxidase, c-myb, and lactoferrin all contained consensus MZF-1 binding sites. An intriguing finding about MZF-1 was its bifunctional transcriptional regulatory activity. In the intracellular environment of adherent, nonhematopoietic cells it functions as a transcriptional repressor, and in hematopoietic cells it functions as an activator.352 

MZF was found to repress the CD34 promoter and the c-myb promoter in nonhematopoietic cells.352,353 However, in one study using the hematopoietic cell lines K562 and Jurkat, MZF-1 activated transcription from the CD34 promoter.352 In another study, using different techniques, it was found that MZF-1 repressed the CD34 promoter in KG-1 cells.353 

The presence of MZF-1 binding sites in several myeloid promoters and the explicit regulation of the CD34 promoter by MZF-1 point out that MZF-1 may have a general role in the regulation of hematopoietic gene expression. Lending evidence to the hypothesis that MZF-1 may be an important regulator of hematopoietic development are studies showing that blocking MZF-1 expression with antisense oligonucleotides inhibits granulopoiesis.347 

MZF-1 can also disrupt the normal proliferative behavior of embryonic fibroblasts. When MZF-1 was retrovirally transduced and overexpressed in NIH 3T3 cells, where it is not normally expressed, it rapidly transformed those cells.354 However, two other myeloid transcriptional regulators, PU.1 and PRH, did not transform 3T3 cells when they were similarly overexpressed. In addition, forced overexpression of MZF-1 in IL-3–dependent FDCP1 or HL-60 cells decreased apoptosis induced by IL-3 withdrawal or retinoic acid, respectively.355 356 FDCP1 cells transduced with MZF-1 formed tumors in 70% of congenic hosts, whereas control cells did not. These data imply that the aberrant expression of nodal regulators of development can be neoplastic. It lends evidence for the hypothesis that malignancy represents normal development gone awry.

The MZF-1 promoter was recently isolated.357 There are MZF-1, PU.1, and retinoic acid receptor binding sites within the MZF-1 promoter.

The early response gene Egr-1.Many groups have isolated Egr-1 (NFGI-A) as an early response gene induced by a variety of stimuli, primarily those that induce cell proliferation.358 Egr-1 was also cloned as an early response gene during TPA treatment of human myeloid cell lines and was noted to be upregulated during monocytic and not granulocytic differentiation of these bipotential lines.25 Overexpression and antisense studies implicated Egr-1 as an inducer of monocytic differentiation.25,359 An Egr-1 knockout mouse line has been made, but no abnormalities of monocytic differentiation or function were detected.360 In this mouse model, it is possible that other members of the Egr-1 family can compensate for loss of the Egr-1 gene.

The Wilms' tumor suppressor gene WT-1.An enlarging body of literature suggests a role for the WT1 Wilms' tumor suppressor gene in normal and leukemic myeloid development. WT1 encodes a zinc finger transcription factor that binds to a GC-rich sequence similar to that of the Egr-1 protein (reviewed previously361 ).362 WT1 can both activate and repress transcription and in model systems inhibits cell growth363-365 and can induce programmed cell death.361,366 WT1 is expressed in normal bone marrow, particularly in CD34+ progenitor cells.367,368 CD43+/CD33/lin cells, believed to be very early progenitors, express the highest levels of WT1, whereas the CD33+ subset of CD34+ progenitors, reflecting a later point in differentiation, express 100-fold less WT1. WT1 is also expressed in the murine embryonic yolk sac and liver during definitive hematopoiesis.368 WT1 is expressed in a number of myeloid cell lines, and WT1 expression is downregulated in HL-60 and K562 cells at the posttranscriptional level during differentiation of these cell lines.369,370 Given that WT1 can compete for the binding site of Egr-1 and repress transcription and that Egr-1 is an activator that promotes monocytic differentiation,25,359 it is possible that the interplay between these two factors, which have opposing transcriptional effects, may play a role in the tight control of monocytic differentiation. The hypothesized role of WT1 in hematopoiesis must be tempered by the results of Kriedberg et al,371 who performed a targeted disruption of the WT1 gene in the mouse. These animals exhibited complete kidney and genitourinary agenesis, defects in the mesothelium, and cardiac defects, but to date have demonstrated no hematopoietic deficits (J. Kreidberg, personal communication, June 1996).

WT1 mRNA expression has been detected in up to 80% of cases of acute myelogenous leukemia.372,373 Whereas WT1 can be found in the marrow of normal subjects, expression in the peripheral blood is distinctly abnormal and a sign of the presence of leukemic cells.367 In addition, there was found to be a negative correlation between WT1 expression and prognosis.367 Reverse transcription-PCR (RT-PCR) assay for WT1 expression can detect minimal residual leukemic blast cells in leukemia patients and may be more sensitive than the detection of fusion gene products such as the PML-RARα fusion found in APL.367,374 There is an inherent paradox in these findings. WT1 is believed to be a classical tumor-suppressor gene, and yet it is expressed in high levels in actively proliferating leukemia. This expression may reflect the stage of differentiation of the malignant cells at the point of transformation. Alternatively, WT1 may have an oncogenic effect when overexpressed in hematopoietic tissue. Recent data indicate that WT1 expression may be important for leukemic cell growth. When myeloid leukemic cell lines were treated with antisense WT1 oligonucleotides, cellular proliferation was inhibited and programmed cell death was induced.375,376 In addition, fresh human leukemia sample growth was inhibited by these antisense WT1 oligonucleotides.376 Mutation of WT1 may also play a role in leukemogenesis. Initially, a mutation was detected in the remaining WT1 allele of a WAGR patient who had been previously treated for Wilms' tumor.377 This mutation affected a cysteine residue in the zinc finger region and would be predicted to abolish DNA binding by WT1. This suggested that complete loss of WT1 function in the myeloid lineage might be associated with the development of leukemia. More recent data from this same group indicate that 15% of cases of AML have point mutations of WT1.320 These were heterozygous mutations leading to the formation of truncated forms of WT1 devoid of zinc finger DNA-binding motifs. Such truncated proteins may act in a dominant negative manner to inhibit the transcriptional effects of wild-type WT1.378-380 This again suggests that WT1 may play a role in the control of leukemic cell growth.

The mechanism of action of WT1 in affecting myeloid growth is not defined, but one important candidate target gene is c-myb, which contains an Egr-1 site within its promoter. This site acts as a negative regulatory element. WT1 binds to this site in vitro and can repress the c-myb promoter.381 This is intriguing given that forced expression of c-myb blocks myeloid differentiation, and treatment of myeloid cells with antisense c-myb oligonucleotides blocks proliferation.42,382 383 WT1 could therefore affect myeloid growth indirectly through action on c-myb.

The homeobox genes are a group of proteins defined by a specific helix-turn-helix DNA binding motif, the homeo domain.313,384,385 These regulators have been shown by mutational and knockout studies to play a major role in segmental development of many species, from Drosophila to mouse.308,386 The genomic organization of these genes in mammals, including humans, is arranged in four clusters that are expressed in a temporal fashion related to their physical position in the cluster. Recently, a number of exciting studies have shown that this class of proteins may indeed influence myeloid development.308,313 A number of studies have investigated the hematopoietic expression of homeobox genes, including ones expressed in stem cells.32 One of these, HoxA10, was noted to be expressed specifically in myeloid cells.309 Subsequent studies showed that HoxA10 mRNA was expressed at higher levels in human CD34+ cells than other homeobox genes and downregulated during myeloid development.32,33 Expression could not be detected in mature neutrophils and monocytes. These studies suggest that HoxA10 is upregulated and then downregulated as stem cells differentiate into mature myeloid cells.387 Interestingly, HoxA10 was detected in a variety of cases of myeloid leukemia, except for APL (M3), and decreased in lymphoid blast crisis of chronic myelogenous leukemia (CML).33 HoxA10 was localized to chromosome 7p14-21.33 Its expression was detected in several cases of monosomy 7, so complete loss of HoxA10 in this abnormality, frequently seen in AML, is not the mechanism of leukemogenesis. Although the targets of HoxA10 are not known, its function has been investigated by overexpression studies using retroviral infection of murine bone marrow.313 388 Overexpression of HoxA10 led to abnormalities of progenitor cells, with increased numbers of megakaryocytic and blast colonies in vitro and increased myeloid progenitors in vivo, but peripheral blood counts were normal. A substantial number of lethally irradiated congenic transplant recipients developed acute myelogenous leukemia, with high blast counts, 5 to 10 months posttransplantation.

In addition to overexpression studies, the function of HoxA10 has been investigated by knockout experiments. Mice with targeted disruption of HoxA10 are fully viable but have defects in both male and female fertility.389 Investigation of the hematopoietic system of these mice showed an increase in peripheral blood neutrophils and monocytes to a level twofold that of wild-type or heterozygote littermates.387 Interestingly, investigation of CFU in the knockout animals showed no change in numbers of GM, M, or GEMM colonies, but these myeloid CFU were extremely large in size, with a fivefold increase in cell number, and contained a preponderance of immature myeloblastic cells.387 In summary, these studies emphasize the role of HoxA10 in myeloid development and make it likely that HoxA10 plays a critical role in control of proliferation at the myeloblastic or promyelocytic stage. Recently, the effects of targeted disruption of the HoxA9 gene have been described.390 HoxA9 is expressed at high levels in human CD34+ cells and myeloid progenitors, but at lower levels in CD34 cells. It is also expressed in lymphocytes. Disruption of HoxA9 resulted in a 30% to 40% reduction in lymphocytes and granulocytes and a blunted response to G-CSF, suggesting a role for HoxA9 at the level of committed progenitors.390 

A number of other homeobox genes have been studied by overexpression and antisense studies, and many of these are of direct relevance to myeloid development. Several of these studies, like those of HoxA10, suggest that downregulation of homeobox genes in progenitors may be important for myeloid maturation. Overexpression of HoxB8, when combined with high levels of IL-3, can induce myeloid leukemia in mice.391 These studies suggested that two events were necessary for leukemogenesis: an increase in progenitor proliferation, mediated by IL-3, and a block in myeloid differentiation, mediated by increased HoxB8 expression.392 Consistent with the notion that downregulation of homeobox genes may be necessary for proper differentiation, antisense studies directed at a diverged homeobox gene expressed in CD34+ cells, HB24, was shown to block IL-3– and GM-CSF–induced proliferation, and overexpression inhibited differentiation. Interestingly, increased expression of HB24 was seen in some cases of AML.393 Another negative regulator of myeloid gene expression that is downregulated with myeloid differentiation, the CDP protein discussed above, is a homeobox protein.229 The HoxB6 gene is expressed in erythroid cells, and blocking its expression with antisense oligonucleotides can induce myeloid differentiation of erythroid lines.312 These studies suggest that HoxB6, like GATA-1, may serve as a switch to direct multipotential progenitors from the myeloid to the erythroid lineage (see discussion below).

In contrast to the studies cited above, in which the homeobox is either downregulated in mature myeloid cells or expressed in other lineages, several studies have looked at homeobox genes expressed in mature myeloid cells. Hlx is expressed in macrophages and neutrophils, and overexpression using a retroviral construct induces myeloid maturation.394 HoxB7 was shown to be induced during vitamin D3 monocytic differentiation of promyelocytic HL-60 cells.395 Overexpression of HoxB7 inhibited neutrophilic differentiation of HL-60 cells, and antisense inhibited GM-CFU.395 PRH (HEX) is an orphan homeobox gene initially identified by three groups using PCR with degenerate primers to conserved homeodomain sequences.359,396,397 PRH is located on human chromosome 10, where HOX 11 is also located.396 PRH is downregulated by TPA-induced monocytic differentiation, but not by retinoic acid-induced granulocytic differentiation.398 PRH is not oncogenic when transduced into 3T3 cells.354 

Finally, regulators of homeobox genes may play important roles in myeloid development and leukemia. The MLL (Hrx) gene, a regulator of homeobox genes,399 is implicated in mixed lineage (lymphoid/myeloid) leukemia.399-401 Another modulator of homeobox function is the Pbx1 gene.402 A fusion protein formed between E2A and Pbx contributes to the t(1:19) pre-B–cell ALL, but expression of the E2A-Pbx fusion protein in mice induces myeloid leukemia.403 Pbx1 binds cooperatively to HoxB4, B6, and B7, all of which have been implicated in myeloid development, as described above, but not to HoxA10.402 In summary, there are many studies implicating homeobox genes in normal myeloid development and leukemia, and the next several years should lead to exciting new developments.

A number of other transcription factors have been implicated in myeloid development or leukemia. Because of space limitations, they shall only be briefly mentioned.

c-myb.Myb was first isolated as a retroviral oncogene and as an Ets fusion protein can transform chicken hematopoietic cells, resulting in a variety of different leukemias.12a,404,405 C-myb is a sequence-specific transcription activator.406 In hematopoietic cells, it is expressed in proliferating progenitors and downregulated with differentiation, with a preferred if not specific expression pattern in myeloid cells.42 This downregulation is important for differentiation of myeloid cell lines.382,383 Knockout of the c-myb gene results in embryonic lethality with a failure of hematopoiesis of fetal liver,29 and c-myb has been shown to be capable of transactivating the CD34 gene in cotransfection studies.407 However, deletion of the c-myb binding sites does not result in significant loss of human CD34 promoter activity,408 and murine CD34 is reportedly expressed at normal levels in c-myb knockout mice,409 so the mechanism by which c-myb regulates CD34 is unclear at this time. Recently, c-myb has been shown to regulate the CD13 gene in myeloid cells410 and downregulate the M-CSF receptor.164 Finally, myb can interact with the AML1 family of transcription factors247 and can synergize with C/EBP to transactivate a myeloid promoter, neutrophil elastase.88 Myb can also cooperate with C/EBP factors to activate target genes in myeloid cells, possibly mediated through the p300/CBP coactivator.197,411,412 All of these results point to an important role of c-myb in myeloid development. In addition, c-myb has been reported to regulate c-myc expression,413 and some of its effects on myeloid development could be mediated through this mechanism (see below).

c-myc.C-myc was isolated as an oncogene whose dysregulation plays a role in avian and human lymphomas. It is a sequence-specific transcription factor and implicated in many processes involving tumorigenesis and apoptosis.12a,373,414,415 Of specific relevance to this review are early studies showing that myc is downregulated in myeloid cell lines as they are induced to differentiate and that treatment of these lines with antisense oligos induces myeloid differentiation.41 Activation of an inducible myc-estrogen receptor construct in a myeloid line can block differentiation.416 Another aspect of c-myc that may be important in myeloid differentiation is that it has been shown to heterodimerize with a number of partners. Dimerization with max leads to transcriptional activation, and dimerization with mad leads to loss of transcriptional activity. It has been shown that mad can be induced with maturation of myeloid cell lines, consistent with the loss of proliferation in these cells.417,418 Finally, a third interesting aspect of myc is that it has been shown to repress the C/EBPα promoter in adipocytes.193 C/EBPα expression increases with adipocyte differentiation as c-myc decreases, and blocking myc function can increase C/EBPα expression and differentiation. Whether c-myc plays a similar role in myeloid expression of C/EBPα is not clear at this time.

NF-κB and rel proteins.In addition to being a major regulator of lymphoid activation, NF-κB has been shown to be activated in myeloid cell lines induced toward monocytic differentiation with TPA. It is thought that this activation may play an important role in human immunodeficiency virus (HIV) replication and production of cytokines, such as macrophage inflammatory protein-1α.419,420 The NF-κB and related rel proteins can interact with C/EBP proteins and as such may modulate the role of C/EBP factors in myeloid cells.210,211,421 Targeted disruption of the relB gene leads to myeloid hyperplasia, suggesting a role for this family in myeloid development.422 

Mixed lineage leukemia (MLL) protein.The MLL protein (also known as Hrx or All-1) has been shown to be involved in translocations of 11q23 associated with mixed (myeloid and lymphoid) leukemia.12a,399-401,423,424 MLL is a very large transcription factor with a number of different motifs, including a SET domain found in the trithorax and polycomb genes, which regulate homeobox gene expression in Drosophila. MLL has activation and repression domains, and the translocations of the MLL gene suggest that loss of the activation and retention of the repression domains could alter the expression of as yet unidentified target genes as a mechanism of leukemogenesis.425 The knockout of the MLL gene caused altered Hox expression and segmental identity, with myeloid defects in heterozygote animals.399 In addition, MLL or All-1 −/− ES cell show a block in maturation during CFU formation in vitro, suggesting that normal function of this gene is important for hematopoietic differentiation.426 

p53.The p53 protein is a tumor-suppressor gene involved in many types of cancer and thought to play a normal role in elimination of cells that have damaged genomes. p53 has been showed to be mutated in many types of human leukemia, including myeloid leukemias.427,428 Other studies have implicated mutations of p53 in CML, particularly in blast crisis.429 p53 has also been shown to be a sequence specific transcriptional activator that can activate target genes, such as the cyclins.430 Wild-type p53 has been shown to induce differentiation of myeloid cell lines.431 Therefore, it is likely that loss of p53 function plays an important role in leukemogenesis.

c-Jun.The c-jun proto-oncogene forms a heterodimer with c-fos to form the AP-1 transcription factor, which has been shown to be involved in cell proliferation and activation.432 C-jun is an early response gene in differentiating myeloid cells, and its expression is upregulated in myeloid cell lines during differentiation.433,434 One known myeloid target is the macrophage scavenger receptor.166 AP-1 is antagonized by the retinoic acid receptor,435 but the PML/RAR fusion protein found in APL is an activator of c-jun, and this may contribute to the proliferative status of the leukemic cells.436 C-jun can also physically interact with PU.1151; this interaction may be important during myeloid differentiation.

The study of myeloid promoter elements has suggested several models of how myeloid genes are regulated. In addition, these studies suggest a model of how myeloid differentiation might be directed by transcription factors in normal cells and how abnormal function of transcription factors may play a role in leukemia. There is a strikingly similar promoter geography of three myeloid CSF receptor promoters, all of which use C/EBP and PU.1 sites (Fig 2). There is likely significant redundancy of some CSF pathways, in that different myeloid CSFs can direct myeloid CFU formation in vitro and that knockout studies of some CSFs, such as GM-CSF, did not show significant hematopoietic abnormalities. However, single transcription factors, such as C/EBPα and/or PU.1, could affect the myeloid lineage by regulating expression of multiple CSF receptors. Alternatively, a factor such as AML1, which is expressed at high levels in T cells in addition to myeloid cells,437 could possibly regulate not only myeloid CSF receptors, such as the M-CSF receptor, but also CSFs produced in T cells that bind to those receptors, such as GM-CSF258 and IL-3.260 

Fig. 2.

Structure of the human myeloid CSF receptor promoters. As with many myeloid promoters, relatively small regions direct activity and specificity in transient transfection studies; in addition, there is no well-defined TATA box. The major transcription start site is designated by the horizontal arrow. Shown are the locations of binding sites for PU.1, C/EBP, and AML1. The PU.1 site in the G-CSF receptor promoter is located in the 5′ untranslated region, at bp +3653; a functional PU.1 site is also found in the 5′ UT region of the PU.1 promoter.55 In unstimulated myeloid cell lines, the major C/EBP gene product is C/EBPα.53,54,215 In newborn livers from C/EBPα −/− animals, only expression of the G-CSF receptor is significantly reduced.28 In PU.1 −/− animals and ES cells, expression of the M-CSF receptor is significantly reduced or undetectable.162 163 

Fig. 2.

Structure of the human myeloid CSF receptor promoters. As with many myeloid promoters, relatively small regions direct activity and specificity in transient transfection studies; in addition, there is no well-defined TATA box. The major transcription start site is designated by the horizontal arrow. Shown are the locations of binding sites for PU.1, C/EBP, and AML1. The PU.1 site in the G-CSF receptor promoter is located in the 5′ untranslated region, at bp +3653; a functional PU.1 site is also found in the 5′ UT region of the PU.1 promoter.55 In unstimulated myeloid cell lines, the major C/EBP gene product is C/EBPα.53,54,215 In newborn livers from C/EBPα −/− animals, only expression of the G-CSF receptor is significantly reduced.28 In PU.1 −/− animals and ES cells, expression of the M-CSF receptor is significantly reduced or undetectable.162 163 

Close modal

The M-CSF receptor promoter itself is a good example of how combinations of factors, not exclusively myeloid-specific, can act together to generate a myeloid-specific promoter (Fig 1). In the case of the M-CSF receptor promoter, there are adjacent binding sites for PU.1,117 which is expressed in myeloid and B cells95,124; AML1, expressed in all white blood cells234,437; and C/EBP, expressed in myeloid cells and not lymphocytic cells.52,195,199 The common cell type in which all three of these factors are expressed is myeloid and not lymphocytic cells. In addition to a shared specificity of expression in myeloid cells, AML1 and C/EBP215 can interact physically in a specific manner and can synergize to activate the M-CSF receptor.215 C/EBP and PU.1 can also physically interact in a specific way.88 142 Therefore, the combinatorial effect of these factors is enhanced.

The findings described in this review of how these transcription factors function suggest a model of how they may direct myeloid development. This model suggests that the apparently irreversible pattern of hematopoietic lineage development may proceed in three steps (Fig 3). (1) In stem cells or more likely early multipotential progenitors, processes that are not defined yet result in the activation of a specific transcription factor, such as GATA-1 or PU.1. (2) Increased activation of expression and/or function of this factor leads to increased expression of a specific growth factor receptor and at the same time through an autoregulatory mechanism increases expression of the specific transcription factor. (3) Further differentiation is mediated by the influence of the specific growth factor, augmented by the upregulation or downregulation of other differentiation genes regulated by the transcription factor.

Fig. 3.

Model of induction of hematopoietic differentiation by specific transcription factors. In this model, transcription factors are expressed at low levels in CD34+ stem cells,134 as are specific growth factor receptors. Under direction of signals that are as yet not defined, such as the influence of stromal interactions or growth factor signalling, specific transcription factors, such as GATA-1 or PU.1,44 are upregulated. Upregulation of specific transcription factors leads to their autoregulation and upregulation of specific growth factor receptors, resulting in increases in proliferation, differentiation, and suppression of apoptosis of specific lineages. Downregulation of specific factors (such as GATA-1 during myeloid development) may also play an important role.

Fig. 3.

Model of induction of hematopoietic differentiation by specific transcription factors. In this model, transcription factors are expressed at low levels in CD34+ stem cells,134 as are specific growth factor receptors. Under direction of signals that are as yet not defined, such as the influence of stromal interactions or growth factor signalling, specific transcription factors, such as GATA-1 or PU.1,44 are upregulated. Upregulation of specific transcription factors leads to their autoregulation and upregulation of specific growth factor receptors, resulting in increases in proliferation, differentiation, and suppression of apoptosis of specific lineages. Downregulation of specific factors (such as GATA-1 during myeloid development) may also play an important role.

Close modal

Both GATA-1 and PU.1 activate important growth factor receptors for the erythroid and myeloid lineages, respectively. For example, during erythroid development from multipotential progenitors, GATA-1 is activated (and PU.1 is repressed).44,438 Previous studies have shown that GATA-1, which plays a key role in erythroid development,5 can transactivate its own promoter.439 Among its many gene targets, GATA-1 can stimulate expression of the erythropoietin receptor.440 It is possible that GATA-1 activation initiates an irreversible differentiation process in which GATA-1 stimulates its own expression and that of the erythropoietin receptor, allowing that progenitor to proliferate and survive in the presence of erythropoietin.

Conversely, activation of PU.1 (and repression of GATA-144,438 ) in a progenitor may lead to stimulation of PU.1 expression through an autoregulatory loop,55 as well as the M-CSF receptor,117 allowing that progenitor to proceed along the path of myeloid development. This model would also suggest that downregulation of GATA-1 during myeloid differentiation and of PU.1 during erythroid commitment might also be important. Consistent with this concept are results suggesting that overexpression of GATA-1 in multipotential cell lines result in a block of myeloid differentiation81,441 and the finding that overexpression of PU.1 due to Friend virus insertion near the Spi-1 locus in early erythroblasts leads to a block in erythroid differentiation and murine erythroleukemia.37,38,125,126 A final addition to this model would be findings showing that GATA-1 and PU.1 could downregulate each other. Although there is a GA-rich sequence in the proximal GATA-1 promoter, PU.1 reportedly does not bind to this region.439 There is a site in the proximal PU.1 promoter that binds to GATA-1 and GATA-2, and coexpression of either GATA protein results in a twofold repression in PU.1 expression in myeloid and nonmyeloid lines.55 The role of this site in downregulation of PU.1 in early myeloid cells remains to be determined. Finally, this model is consistent with findings indicating that GATA-1 does not play a major role in myeloid development5 and that GATA-2 is either not expressed in or downregulated in myeloid cells.78 Other myeloid promoters, such as CD11b,76 also have sites in their promoters that bind GATA-1 and GATA-2, but are not functional as assessed either by transient analysis of specific point mutations or by transactivation studies.116 

Recent findings suggest that C/EBP factors, notably C/EBPα, may also contribute to myeloid development using mechanisms similar to the model invoking GATA and PU.1. It is not yet known how C/EBP proteins are regulated during multilineage development of CD34+ cells, but it does appear to be selectively expressed at high levels in neutrophilic and not monocytic or erythroid cells (H.S. Radomska and D.G. Tenen, manuscript submitted). If it is upregulated selectively during neutrophilic development, it may also be autoregulated in these cells as it is in adipocytes.192,194 It is known to augment expression of the G-CSF receptor promoter53 and by this mechanism could promote the development of neutrophilic cells in a manner similar to that described above for PU.1 and GATA-1 for the monocytic and erythroid lineages, respectively.

In this review, we have attempted to summarize what is known about myeloid transcription factors, lineage development, and differentiation. Clearly many advances have been made in the last few years, but many very important questions remain unanswered.

How do the combinations of these myeloid transcription factors make a specific lineage? Although we have provided some concepts based on studies of the M-CSF receptor, clearly other genes are regulated by other combinations of factors.

What differences among myeloid subtypes (monocytes, neutrophils, and eosinophils) are determined by transcription factors? An example is the role of C/EBPα in neutrophilic development.

How are the regulators (PU.1, C/EBPα, etc) themselves regulated in stem cells and multipotential progenitors? Are they activated by cytokines or other extrinsic signals, or is the process stochastic and autoregulatory? Are they in turn regulated by other regulators, such as homeobox genes?

Are there truly myeloid locus control regions, scaffold and matrix attachment regions, and other elements that are important for expression of myeloid genes in the proper chromosomal context?

What are the negative regulatory loops? Do repressors like CDP228 or AEBP1231 play a role? What is the role of GATA-1?

Why is it that factors expressed in other lineages (such as PU.1 in B cells) do not induce expression of myeloid genes in those lineages? Is it because combinatorial effects of factors are needed for myeloid expression or because of negative regulation in nonmyeloid cells?

What is the role of myeloid transcription factors in apoptosis? Do they promote myeloid development by inhibition of apoptosis?

How does signalling affect myeloid development? What is the role of Janus kinases (JAKs) and STATs?13,442,443 To date, knockout studies have not shown these factors to be essential for myeloid development. What is the role of hematopoietic cell phosphatase, whose mutation results in increased macrophage production?444,445 What is the role of NF1?446,447

What are the mechanisms of leukemic development? The studies summarized in this review, in which we have characterized targets of myeloid transcription factors and models of how they could induce myeloid development, suggest a number of mechanisms in which abnormalities of myeloid transcription factor function could play a role in myeloid leukemias, which represent a block in early myeloid differentiation. Translating the knowledge of what we understand about myeloid gene regulation to understanding the pathogenesis of leukemia and perhaps developing new therapies will be the major challenge for future studies.

The authors apologize in advance to the many investigators whose work we were unable to cite due to space limitations. We also thank David Hume, Hanna Radomska, Laura Smith, Milton Datta, and Gerhard Behre for their careful reading of the manuscript and thoughtful suggestions and Jim Griffin for his patience.

Supported by National Institutes of Health Grants No. CA41456 and DK48660 (to D.G.T.), HL48914 (to R.H.), CA59936 (to. J.D.L.), and CA59589 (to D.-E.Z.) and by American Cancer Society Grants No. DHP-160 (to J.D.L.) and DHP-166 (to D.-E.Z.). R.H. and J.D.L. are Scholars of the Leukemia Society of America.

Address reprint requests to Daniel G. Tenen, MD, Harvard Institutes of Medicine, Room 954, 77 Avenue Louis Pasteur, Boston, MA 02115.

1
Davis
RL
Weintraub
H
Lassar
AB
Expression of a single transfected cDNA converts fibroblasts to myoblasts.
Cell
51
1987
987
2
Blau
HM
Baltimore
D
Differentiation requires continuous regulation.
J Cell Biol
112
1991
781
3
Shivdasani
RA
Orkin
SH
The transcriptional control of hematopoiesis.
Blood
87
1996
4025
4
Orkin
SH
Transcription factors and hematopoietic development.
J Biol Chem
270
1995
4955
5
Pevny
L
Simon
MC
Robertson
E
Klein
WH
Tsai
SF
D'Agati
V
Orkin
SH
Costantini
F
Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1.
Nature
349
1991
257
6
Warren
AJ
Colledge
WH
Carlton
MB
Evans
MJ
Smith
AJ
Rabbitts
TH
The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development.
Cell
78
1994
45
7
Shivdasani
RA
Mayer
EL
Orkin
SH
Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL.
Nature
373
1995
432
8
Georgopoulos
K
Bigby
M
Wang
JH
Molnar
A
Wu
P
Winandy
S
Sharpe
A
The Ikaros gene is required for the development of all lymphoid lineages.
Cell
79
1994
143
9
Urbanek
P
Wang
ZQ
Fetka
I
Wagner
EF
Busslinger
M
Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP.
Cell
79
1994
901
10
Lubbert
M
Herrmann
F
Koeffler
HP
Expression and regulation of myeloid-specific genes in normal and leukemic myeloid cells.
Blood
77
1991
909
11
Nichols
J
Nimer
SD
Transcription factors, translocations, and leukemia.
Blood
80
1992
2953
12
Rabbitts
TH
Chromosomal translocations in human cancer.
Nature
372
1994
143
12a
Wolff L: Contribution of oncogenes and tumor suppressor genes to myeloid leukemia. Biochim Biophys Acta 1332:F67, 1997
13
Darnell
JE
Kerr
IM
Stark
GR
Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.
Science
264
1994
1415
14
Moreau-Gachelin
F
Spi-1/PU.1: An oncogene of the ets family.
Biochim Biophys Acta
1198
1994
149
15
Kehrl
JH
Hematopoietic lineage commitment: Role of transcription factors.
Stem Cells
13
1995
223
16
Shapiro
LH
Look
AT
Transcriptional regulation in myeloid cell differentation.
Curr Opin Hematol
2
1995
3
17
Nucifora
G
Rowley
JD
AML1 and the 8; 21 and 3; 21 translocations in acute and chronic myeloid leukemia.
Blood
86
1995
1
18
Hagman
J
Grosschedl
R
Regulation of gene expression at early stages of B-cell differentiation.
Curr Opin Immunol
6
1994
222
19
Grignani
F
Fagioli
M
Alcalay
M
Longo
L
Pandolfi
PP
Donti
E
Biondi
A
LoCoco
F
Pelicci
PG
Acute promyelocytic leukemia — From genetics to treatment.
Blood
83
1994
10
20
Metcalf
D
Hematopoietic regulators — Redundancy or subtlety.
Blood
82
1993
3515
21
Roberts
R
Gallagher
J
Spooncer
E
Allen
TD
Bloomfield
F
Dexter
TM
Heparan sulphate bound growth factors: a mechanism for stromal cell mediated haemopoiesis.
Nature
332
1988
376
22
Fairbairn
LJ
Cowling
GJ
Reipert
BM
Dexter
TM
Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors.
Cell
74
1993
823
23
Just
U
Friel
J
Heberlein
C
Tamura
T
Baccarini
M
Tessmer
U
Klinger
K
Ostertag
W
Upregulation of lineage specific receptors and ligands in multipotential prognitor cells is part of an endogenous program of differentiation.
Growth Factors
9
1993
291
24
Pedersen-Bjergaard
J
Rowley
JD
The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation.
Blood
83
1994
2780
25
Nguyen
HQ
Hoffman-Liebermann
B
Liebermann
DA
The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage.
Cell
72
1993
197
26
Scott
EW
Simon
MC
Anastai
J
Singh
H
The transcription factor PU.1 is required for the development of multiple hematopoietic lineages.
Science
265
1994
1573
27
Torbett BE, McKercher SC, Anderson KL, Vestal DJ, Henkel G, Maki RA: The disruption of the gene for the transcription factor PU.1 leads to multiple hematopoietic defects. Blood 86:251a, 1995 (abstr, suppl 1)
28
Zhang
D-E
Zhang
P
Wang
ND
Hetherington
CJ
Darlington
GJ
Tenen
DG
Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein α-deficient mice.
Proc Natl Acad Sci USA
94
1997
569
29
Mucenski
ML
McLain
K
Kier
AB
Swerdlow
SH
Schreiner
CM
Miller
TA
Pietryga
DW
Scott
WJ Jr
Potter
SS
A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis.
Cell
65
1991
677
30
Hromas
R
Collins
SJ
Hickstein
D
Raskind
W
Deaven
LL
O'Hara
P
Hagen
FS
Kaushansky
K
A retinoic acid-responsive human zinc finger gene, MZF-1, preferentially expressed in myeloid cells.
J Biol Chem
266
1991
14183
31
Giampaolo
A
Sterpetti
P
Bulgarini
D
Samoggia
P
Pelosi
E
Valtieri
M
Peschle
C
Key functional role and lineage-specific expression of selected HOXB genes in purified hematopoietic progenitor differentiation.
Blood
84
1994
3637
32
Sauvageau
G
Lansdorp
PM
Eaves
CJ
Hogge
DE
Dragowska
WH
Reid
DS
Largman
C
Lawrence
HJ
Humphries
RK
Differential expression of homeobox genes in functionally distinct CD34(+) subpopulations of human bone marrow cells.
Proc Natl Acad Sci USA
91
1994
12223
33
Lawrence
HJ
Sauvageau
G
Ahmadi
N
Lopez
AR
LeBeau
MM
Link
M
Humphries
K
Largman
C
Stage- and lineage-specific expression of the HOXA10 homeobox gene in normal and leukemic hematopoietic cells.
Exp Hematol
23
1995
1160
34
Coppola
JA
Cole
MD
Constitutive c-myc oncogene expression blocks mouse erythroleukaemia cell differentiation but not commitment.
Nature
320
1986
760
35
Adams
JM
Cory
S
Transgenic models of tumor development.
Science
254
1991
1161
36
Kreider
BL
Benezra
R
Rovera
G
Kadesch
T
Inhibition of myeloid differentiation by the helix-loop-helix protein Id.
Science
255
1992
1700
37
Moreau-Gachelin
F
Tavitian
A
Tambourin
P
Spi-1 is a putative oncogene in virally induced murine erythroleukaemias.
Nature
331
1988
277
38
Paul
R
Schuetze
S
Kozak
SL
Kozak
CA
Kabat
D
The Sfpi-1 proviral integration site of Friend erythroleukemia encodes the ets-related transcription factor Pu.1.
J Virol
65
1991
464
39
Miyoshi
H
Shimizu
K
Kozu
T
Maseki
N
Kaneko
Y
Ohki
M
t(8; 21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1.
Proc Natl Acad Sci USA
88
1991
10431
40
Chen
SJ
Zelent
A
Tong
JH
Yu
HQ
Wang
ZY
Derre
J
Berger
R
Waxman
S
Chen
Z
Rearrangements of the retinoic acid receptor-alpha and promyelocytic leukemia zinc finger genes resulting from t(11-17)(q23-q21) in a patient with acute promyelocytic leukemia.
J Clin Invest
91
1993
2260
41
Holt
JT
Redner
RL
Nienhuis
AW
An oligomer complementary to c-myc mRNA inhibits proliferation of HL-60 promyelocytic cells and induces differentiation.
Mol Cell Biol
8
1988
963
42
Gewirtz
AM
Calabretta
B
A c-myb antisense oligodeoxynucleotide inhibits normal human hematopoiesis in vitro.
Science
242
1988
1303
43
Bavisotto
L
Kaushansky
K
Lin
N
Hromas
R
Antisense oligonucleotides from the stage-specific myeloid zinc finger gene MZF-1 inhibit granulopoiesis in vitro.
J Exp Med
174
1991
1097
44
Voso
MT
Burn
TC
Wulf
G
Lim
B
Leone
G
Tenen
DG
Inhibition of hematopoiesis by competitive binding of the transcription factor PU.1.
Proc Natl Acad Sci USA
91
1994
7932
45
Tsai
S
Collins
SJ
A dominant negative retinoic acid receptor blocks neutrophil differentiation at the promyelocyte stage.
Proc Natl Acad Sci USA
90
1993
7153
46
Shin
MK
Koshland
ME
Ets-related protein PU.1 regulates expression of the immunoglobulin J-chain gene through a novel Ets-binding element.
Genes Dev
7
1993
2006
47
Kominato
Y
Galson
DL
Waterman
WR
Webb
AC
Auron
PE
Monocyte-specific expression of the human prointerleukin 1β gene (IL1β) is dependent upon promoter sequences which bind the hematopoietic transcription factor Spi-1/PU.1.
Mol Cell Biol
15
1995
58
48
Tsai
FY
Keller
G
Kuo
FC
Weiss
M
Chen
J
Rosenblatt
M
Alt
FW
Orkin
SH
An early haematopoietic defect in mice lacking the transcription factor GATA-2.
Nature
371
1994
221
49
Okuda
T
van Deursen
J
Hiebert
SW
Grosveld
G
Downing
JR
AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis.
Cell
84
1996
321
50
Wang
Q
Stacy
T
Binder
M
Marin-Padilla
M
Sharpe
AH
Speck
NA
Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoesis.
Proc Natl Acad Sci USA
93
1996
3444
51
Maniatis
T
Goodbourn
S
Fischer
JA
Regulation of inducible and tissue-specific gene expression.
Science
236
1987
1237
52
Zhang
D-E
Fujioka
KI
Hetherington
CJ
Shapiro
LH
Chen
HM
Look
AT
Tenen
DG
Identification of a region which directs monocytic activity of the colony-stimulating factor 1 (macrophage colony-stimulating factor) receptor promoter and binds PEBP2/CBF (AML1).
Mol Cell Biol
14
1994
8085
53
Smith
LT
Hohaus
S
Gonzalez
DA
Dziennis
SE
Tenen
DG
PU.1 (Spi-1) and C/EBPα regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells.
Blood
88
1996
1234
54
Hohaus
S
Petrovick
MS
Voso
MT
Sun
Z
Zhang
D-E
Tenen
DG
PU.1 (Spi-1) and C/EBPα regulate the expression of the granulocyte-macrophage colony-stimuating factor receptor α gene.
Mol Cell Biol
15
1995
5830
55
Chen
HM
Ray-Gallet
D
Zhang
P
Hetherington
CJ
Gonzalez
DA
Zhang
D-E
Moreau-Gachelin
F
Tenen
DG
PU.1 (Spi-1) autoregulates its expression in myeloid cells.
Oncogene
11
1995
1549
56
Kistler
B
Pfisterer
P
Wirth
T
Lymphoid- and myeloid-specific activity of the PU.1 promoter is determined by the combinatorial action of octamer and ets transcription factors.
Oncogene
11
1995
1095
57
Hagemeier
C
Bannister
AJ
Cook
A
Kouzarides
T
The activation domain of transcription factor PU.1 binds the retinoblastoma (RB) protein and the transcription factor TFIID in vitro: RB shows sequence similarity to TFIID and TFIIB.
Proc Natl Acad Sci USA
90
1993
1580
58
Eichbaum
QG
Iyer
R
Raveh
DP
Mathieu
C
Ezekowitz
AB
Restriction of interferon gamma responsiveness and basal expression of the myeloid human FcgammaR1b gene is mediated by a functional PU.1 site and a transcription initiator consensus.
J Exp Med
179
1994
1985
59
Emili
A
Greenblatt
J
Ingles
CJ
Species-specific interaction of the glutamine-rich activation domains of Sp1 with the TATA box-binding protein.
Mol Cell Biol
14
1994
1582
60
Zwilling
S
Annweiler
A
Wirth
T
The POU domains of the Oct1 and Oct2 transcription factors mediate specific interaction with TBP.
Nucleic Acids Res
22
1994
1655
61
Nerlov
C
Ziff
EB
CCAAT/enhancer binding protein-alpha amino acid motifs with dual TBP and TFIIB binding ability co-operate to activate transcription in both yeast and mammalian cells.
EMBO J
14
1995
4318
62
Roberts
WM
Shapiro
LH
Ashmun
RA
Look
AT
Transcription of the human colony-stimulating factor-1 receptor gene is regulated by separate tissue-specific promoters.
Blood
79
1992
586
63
Fleming
JC
Pahl
HL
Gonzalez
DA
Smith
TF
Tenen
DG
Structural analysis of the CD11b gene and phylogenetic analysis of the alpha-integrin gene family demonstrate remarkable conservation of genomic organization and suggest early diversification during evolution.
J Immunol
150
1993
480
64
Seto
Y
Fukunaga
R
Nagata
S
Chromosomal gene organization of the human granulocyte colony-stimulating factor receptor.
J Immunol
148
1992
259
65
Chen
HM
Pahl
HL
Scheibe
RJ
Zhang
D-E
Tenen
DG
The Sp1 transcription factor binds the CD11b promoter specifically in myeloid cells in vivo and is essential for myeloid-specific promoter activity.
J Biol Chem
268
1993
8230
66
Zhang
D-E
Hetherington
CJ
Tan
S
Dziennis
SE
Gonzalez
DA
Chen
HM
Tenen
DG
Sp1 is a critical factor for the monocytic specific expression of human CD14.
J Biol Chem
269
1994
11425
67
Zhang
D-E
Hetherington
CJ
Gonzalez
DA
Chen
HM
Tenen
DG
Regulation of CD14 expression during monocytic differentiation induced with 1alpha,25-Dihydroxyvitamin D3.
J Immunol
153
1994
3276
68
Saffer
JD
Jackson
SP
Annarella
MB
Developmental expression of Sp1 in the mouse.
Mol Cell Biol
11
1991
2189
69
Darrow
AL
Rickles
RJ
Pecorino
LT
Strickland
S
Transcription factor Sp1 is important for retinoic acid-induced expression of the tissue plasminogen activator gene during F9 teratocarcinoma cell differentiation.
Mol Cell Biol
10
1990
5883
70
Kim
SJ
Onwuta
US
Lee
YI
Li
R
Botchan
MR
Robbins
PD
The retinoblastoma gene product regulates Sp1-mediated transcription.
Mol Cell Biol
12
1992
2455
71
Udvadia
AJ
Rogers
KT
Higgins
PDR
Murata
Y
Martin
KH
Humphrey
PA
Horowitz
JM
Sp-1 binds promoter elements regulated by the RB protein and Sp-1-mediated transcription is stimulated by RB coexpression.
Proc Natl Acad Sci USA
90
1993
3265
72
Chen
LI
Nishinaka
T
Kwan
K
Kitabayashi
I
Yokoyama
K
Fu
YHF
Grunwald
S
Chiu
R
The retinoblastoma gene product RB stimulates Sp1-mediated transcription by liberating Sp1 from a negative regulator.
Mol Cell Biol
14
1994
4380
73
Hagen
G
Muller
S
Beato
M
Suske
G
Sp1-mediated transcriptional activation is repressed by Sp3.
EMBO J
13
1994
3843
74
Zhang
R
Tsai
FY
Orkin
SH
Hematopoietic development of vav(−/−) mouse embryonic stem cells.
Proc Natl Acad Sci USA
91
1994
12755
75
Fischer
KD
Haese
A
Nowock
J
Cooperation of GATA-1 and Sp1 can result in synergistic transcriptional activation or interference.
J Biol Chem
268
1993
23915
76
Pahl
HL
Rosmarin
AG
Tenen
DG
Characterization of the myeloid-specific CD11b promoter.
Blood
79
1992
865
77
Martin
F
Prandini
MH
Thevenon
D
Marguerie
G
Uzan
G
The transcription factor GATA-1 regulates the promoter activity of the platelet glycoprotein-IIb gene.
J Biol Chem
268
1993
21606
78
Lee
ME
Temizer
DH
Clifford
JA
Quertermous
T
Cloning of the GATA-binding protein that regulates endothelin-1 gene expression in endothelial cells.
J Biol Chem
266
1991
16188
79
Zon
LI
Yamaguchi
Y
Yee
K
Albee
EA
Kimura
A
Bennett
JC
Orkin
SH
Ackerman
SJ
Expression of mRNA for the GATA-binding proteins in human eosinophils and basophils: Potential role in gene transcription.
Blood
81
1993
3234
80
Visvader
JE
Elefanty
AG
Strasser
A
Adams
JM
GATA-1 but not SCL induces megakaryocytic differentiation in an early myeloid line.
EMBO J
11
1992
4557
81
Kulessa
H
Frampton
J
Graf
T
GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts.
Genes Dev
9
1995
1250
82
Ferrero
E
Jiao
D
Tsuberi
BZ
Tesio
L
Rong
GW
Haziot
A
Goyert
SM
Transgenic mice expressing human CD14 are hypersensitive to lipopolysaccharide.
Proc Natl Acad Sci USA
90
1993
2380
83
Tenen DG: unpublished data.
84
Ahne
B
Stratling
WH
Characterization of a myeloid-specific enhancer of the chicken lysozyme gene — Major role for an Ets transcription factor-binding site.
J Biol Chem
269
1994
17794
85
Bonifer
C
Vidal
M
Grosveld
F
Sippel
AE
Tissue specific and position independent expression of the complete gene domain for chicken lysozyme in transgenic mice.
EMBO J
9
1990
2843
86
Morishita
K
Tsuchiya
M
Asano
S
Kaziro
Y
Nagata
S
Chromosomal gene structure of human myeloperoxidase and regulation of its expression by granulocyte colony-stimulating factor.
J Biol Chem
262
1987
15208
87
Nuchprayoon
I
Meyers
S
Scott
LM
Suzow
J
Hiebert
S
Friedman
AD
PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2beta/CBFbeta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells.
Mol Cell Biol
14
1994
5558
88
Oelgeschlager
M
Nuchprayoon
I
Luscher
B
Friedman
AD
C/EBP, c-Myb, and PU.1 cooperate to regulate the neutrophil elastase promoter.
Mol Cell Biol
16
1996
4717
89
Sturrock
A
Franklin
KF
Hoidal
JR
Human proteinase-3 expression is regulated by PU.1 in conjunction with a cytidine-rich element.
J Biol Chem
271
1996
32392
90
Grisolano
JL
Sclar
GM
Ley
TJ
Early myeloid cell-specific expression of the human cathepsin G gene in transgenic mice.
Proc Natl Acad Sci USA
91
1994
8989
91
Shapiro
LH
Ashmun
RA
Roberts
WM
Look
AT
Separate promoters control transcription of the human aminopeptidase N gene in myeloid and intestinal epithelial cells.
J Biol Chem
266
1991
11999
92
Avalos
BR
Molecular analysis of the granulocyte colony-stimulating factor receptor.
Blood
88
1996
761
93
Rosmarin
AG
Weil
SC
Rosner
GL
Griffin
JD
Arnaout
MA
Tenen
DG
Differential expression of CD11b/CD18 (Mo1) and myeloperoxidase genes during myeloid differentiation.
Blood
73
1989
131
94
Hickstein
DD
Back
AL
Collins
SJ
Regulation of expression of the CD11b and CD18 subunits of the neutrophil adherence receptor during human myeloid differentiation.
J Biol Chem
264
1989
21812
95
Chen
HM
Zhang
P
Voso
MT
Hohaus
S
Gonzalez
DA
Glass
CK
Zhang
D-E
Tenen
DG
Neutrophils and monocytes express high levels of PU.1 (Spi-1) but not Spi-B.
Blood
85
1995
2918
96
Farokhzad
OO
Shelley
CS
Arnaout
MA
Induction of the CD11b gene during activation of the monocytic cell line U937 requires a novel nuclear factor MS-2.
J Immunol
157
1996
5597
97
Wu
H
Moulton
K
Horvai
A
Parik
S
Glass
CK
Combinatorial interactions between AP-1 and ets domain proteins contribute to the developmental regulation of the macrophage scavenger receptor gene.
Mol Cell Biol
14
1994
2129
98
Tsukada
J
Saito
K
Waterman
WR
Webb
AC
Auron
PE
Transcription factors NF-IL6 and CREB recognize a common essential site in the human prointerleukin 1β gene.
Mol Cell Biol
14
1994
7285
99
Tsukada
J
Waterman
WR
Koyama
Y
Webb
AC
Auron
PE
A novel STAT-like factor mediates lipopolysaccharide, interleukin 1 (IL-1), and IL-6 signaling and recognizes a gamma interferon activation site-like element in the IL1B gene.
Mol Cell Biol
16
1996
2183
100
Kozak
M
An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNAs.
Nucleic Acids Res
15
1987
8125
101
Hehlgans
T
Strominger
JL
Activation of transcription by binding of NF-E1 (YY1) to a newly identified element in the first exon of the human DR alpha gene.
J Immunol
154
1995
5181
102
Grosveld
F
van Assendelft
GB
Greaves
DR
Kollias
G
Position-independent, high-level expression of the human beta-globin gene in transgenic mice.
Cell
51
1987
975
103
Skalnik
DG
Dorfman
D
Perkins
AS
Jenkins
NA
Copeland
NG
Orkin
SH
Targeting of transgene expression to monocyte/macrophages by the gp91-phox promoter and consequent histiocytic malignancies.
Proc Natl Acad Sci USA
88
1991
8505
104
Greer
P
Maltby
V
Rossant
J
Bernstein
A
Pawson
T
Myeloid expression of the human c-fps/fes proto-oncogene in transgenic mice.
Mol Cell Biol
10
1990
2521
105
Bonifer
C
Yannoutsos
N
Kruger
G
Grosveld
F
Sippel
AE
Dissection of the locus control function located on the chicken lysozyme gene domain in transgenic mice.
Nucleic Acids Res
22
1994
4202
106
Miyazaki
T
Suzuki
G
Yamamura
K-I
The role of macrophages in antigen presentation and T cell tolerance.
Int Immunol
5
1993
1023
107
Jin
DI
Jameson
SB
Reddy
MA
Schenkman
D
Ostrowski
MC
Alterations in differentiation and behavior of monocytic phagocytes in transgenic mice that express dominant suppressors of ras signaling.
Mol Cell Biol
15
1995
693
108
Lagasse
E
Weissman
IL
bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages.
J Exp Med
179
1994
1047
109
Brown
D
Kogan
S
Lagasse
E
Weissman
IL
Alcalay
M
Pelicci
PG
Atwater
S
Bishop
JM
A PMLRARα transgene initiates murine acute promyelocytic leukemia.
Proc Natl Acad Sci USA
94
1997
2551
110
Clarke
S
Greaves
DR
Chung
LP
Tree
P
Gordon
S
The human lysozyme promoter directs reporter gene expression to activated myelomonocytic cells in transgenic mice.
Proc Natl Acad Sci USA
93
1996
1434
111
Dziennis
S
Tenen
DG
The CD11b promoter directs high-level expression of reporter genes in macrophages in transgenic mice.
Blood
85
1995
1983
112
Back
A
East
K
Hickstein
D
Leukocyte integrin CD11b promoter directs expression in lymphocytes and granulocytes in transgenic mice.
Blood
85
1995
1017
113
Early
E
Moore
MAS
Kakizuka
A
Nason-Burchenal
K
Martin
P
Evans
RM
Dmitrovsky
E
Transgenic expression of PML/RARα impairs myelopoiesis.
Proc Natl Acad Sci USA
93
1996
7900
114
De Sepulveda
P
Salaun
P
Maas
N
Andre
C
Panthier
JJ
SARs do not impair position-dependent expression of a kit/lacZ transgene.
Biochem Biophys Res Commun
211
1995
735
115
Grisolano
JL
Wesselschmidt
RL
Pelicci
PG
Ley
TJ
Altered myeloid development and acute leukemia in transgenic mice expressing PML-RARα under control of cathepsin G regulatory sequences.
Blood
89
1997
376
116
Pahl
HL
Scheibe
RJ
Zhang
D-E
Chen
HM
Galson
DL
Maki
RA
Tenen
DG
The proto-oncogene PU.1 regulates expression of the myeloid-specific CD11b promoter.
J Biol Chem
268
1993
5014
117
Zhang
D-E
Hetherington
CJ
Chen
HM
Tenen
DG
The macrophage transcription factor PU.1 directs tissue specific expression of the macrophage colony stimulating factor receptor.
Mol Cell Biol
14
1994
373
118
Ray-Gallet
D
Mao
C
Tavitian
A
Moreau-Gachelin
F
DNA binding specificities of Spi-1/PU.1 and Spi-B transcription factors and identification of a Spi-1/Spi-B binding site in the c-fes/c-fps promoter.
Oncogene
11
1995
303
119
Heydemann
A
Juang
G
Hennessy
K
Parmacek
MS
Simon
MC
The myeloid cell-specific c-fes promoter is regulated by Sp1, PU.1, and a novel transcription factor.
Mol Cell Biol
16
1996
1676
120
Horvai
A
Palinski
W
Wu
H
Moulton
KS
Kalla
K
Glass
CK
Scavenger receptor A gene regulatory elements target gene expression to macrophages and to foam cells of atherosclerotic lesions.
Proc Natl Acad Sci USA
92
1995
5391
121
Krall
WJ
Challita
PM
Perlmutter
LS
Skelton
DC
Kohn
DB
Cells expressing human glucocerebrosidase from a retroviral vector repopulate macrophages and central nervous system microglia after murine bone marrow transplantation.
Blood
83
1994
2737
122
Bauer
TR
Osborne
WRA
Kwok
WW
Hickstein
DD
Expression from leukocyte integrin promoters in retroviral vectors.
Hum Gene Ther
5
1994
709
123
Malik
P
Krall
WJ
Yu
XJ
Zhou
C
Kohn
DB
Retroviral-mediated gene expression in human myelomonocytic cells: A comparison of hematopoietic cell promoters to viral promoters.
Blood
86
1995
2993
124
Klemsz
MJ
McKercher
SR
Celada
A
Van Beveren
C
Maki
RA
The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene.
Cell
61
1990
113
125
Schuetze
S
Stenberg
PE
Kabat
D
The Ets-related transcription factor PU.1 immortalizes erythroblasts.
Mol Cell Biol
13
1993
5670
126
Moreau-Gachelin
F
Wendling
F
Molina
T
Denis
N
Titeux
M
Grimber
G
Briand
P
Vainchenker
W
Tavitian
A
Spi-1/PU.1 transgenic mice develop multistep erythroleukemias.
Mol Cell Biol
16
1996
2453
127
Delgado
MD
Hallier
M
Meneceur
P
Tavitian
A
Moreau-Gachelin
F
Inhibition of friend cells proliferation by spi-1 antisense oligodeoxynucleotides.
Oncogene
9
1994
1723
128
Karim
FD
Urness
LD
Thummel
CS
Klemsz
MJ
McKercher
SR
Celada
A
Van Beveren
C
Maki
RA
Gunther
CV
Nye
JA
Graves
BJ
The ETS-domain: A new DNA-binding motif that recognizes a purine-rich core DNA sequence.
Genes Dev
4
1990
1451
129
Wasylyk
B
Hahn
SL
Giovane
A
The Ets family of transcription factors.
Eur J Biochem
211
1993
7
130
Ray
D
Bosselut
R
Ghysdael
J
Mattei
MG
Tavitian
A
Moreau-Gachelin
F
Characterization of Spi-B, a transcription factor related to the putative oncoprotein Spi-1/PU.1.
Mol Cell Biol
12
1992
4297
131
Klemsz
MJ
Maki
RA
Activation of transcription by PU.1 requires both acidic and glutamine domains.
Mol Cell Biol
16
1996
390
132
Weintraub
SJ
Chow
KN
Luo
RX
Zhang
SH
He
S
Dean
DC
Mechanism of active transcriptional repression by the retinoblastoma protein.
Nature
375
1995
812
133
Kodandapani
R
Pio
F
Ni
CZ
Piccialli
G
Klemsz
M
McKercher
S
Maki
RA
Ely
KR
A new pattern for helix-turn-helix recognition revealed by the PU.1 ETS-domain-DNA complex.
Nature
380
1996
456
134
Cheng
T
Shen
H
Giokas
D
Gere
J
Tenen
DG
Scadden
DT
Temporal Mapping of gene expression levels during the differentiation of individual primary hematopoietic cells.
Proc Natl Acad Sci USA
93
1996
13158
135
Hromas
R
Orazi
A
Neiman
RS
Maki
R
Vanbeveran
C
Moore
J
Klemsz
M
Hematopoietic lineage-restricted and stage-restricted expression of the ETS oncogene family member PU.1.
Blood
82
1993
2998
136
Schuetze
S
Paul
R
Gliniak
BC
Kabat
D
Role of the PU.1 transcription factor in controlling differentiation of Friend erythroleukemia cells.
Mol Cell Biol
12
1992
2967
137
Galson
DL
Hensold
JO
Bishop
TR
Schalling
M
D'Andrea
AD
Jones
C
Auron
PE
Housman
DE
Mouse beta-globin DNA-binding protein B1 is identical to a proto-oncogene, the transcription factor Spi-1/PU.1, and is restricted in expression to hematopoietic cells and the testis.
Mol Cell Biol
13
1993
2929
138
Chen
HM
Zhang
P
Radomska
HS
Hetherington
CJ
Zhang
D-E
Tenen
DG
Octamer binding factors and their coactivator can activate the murine PU.1 (spi-1) promoter.
J Biol Chem
271
1996
15743
139
Oka
T
Rairkar
A
Chen
JH
Structural and functional analysis of the regulatory sequences of the ets-1 gene.
Oncogene
6
1991
2077
140
Hensold
JO
Stratton
CA
Barth
D
Galson
DL
Expression of the transcription factor, Spi-1 (PU.1), in differentiating murine erythroleukemia cells is regulated post-transcriptionally — Evidence for differential stability of transcription factor mrnas following inducer exposure.
J Biol Chem
271
1996
3385
141
Wasylyk
C
Kerckaert
JP
Wasylyk
B
A novel modulator domain of Ets transcription factors.
Genes Dev
6
1992
965
142
Nagulapalli
S
Pongubala
JM
Atchison
ML
Multiple proteins physically interact with PU.1.
J Immunol
155
1995
4330
143
Pongubala
JM
Nagulapalli
S
Klemsz
MJ
McKercher
SR
Maki
RA
Atchison
ML
PU.1 recruits a second nuclear factor to a site important for immunoglobulin kappa 3′ enhancer activity.
Mol Cell Biol
12
1992
368
144
Pongubala
JM
Van Beveren
C
Nagulapalli
S
Klemsz
MJ
McKercher
SR
Maki
RA
Atchison
ML
Effect of PU.1 phosphorylation on interaction with NF-EM5 and transcriptional activation.
Science
259
1993
1622
145
Eisenbeis
CF
Singh
H
Storb
U
PU.1 is a component of a multiprotein complex which binds an essential site in the murine immunoglobulin lambda-2-4 enhancer.
Mol Cell Biol
13
1993
6452
146
Eisenbeis
CF
Singh
H
Storb
U
Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator.
Genes Dev
9
1995
1377
147
Wang
CY
Petryniak
B
Thompson
CB
Kaelin
WG
Leiden
JM
Regulation of the Ets-related transcription factor Elf-1 by binding to the retinoblastoma protein.
Science
260
1993
1330
148
Chen
PL
Scully
P
Shew
JY
Wang
JY
Lee
WH
Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation.
Cell
58
1989
1193
149
Furukawa
Y
DeCaprio
JA
Freedman
A
Kanakura
Y
Nakamura
M
Ernst
TJ
Livingston
DM
Griffin
JD
Expression and state of phosphorylation of the retinoblastoma susceptibility gene product in cycling and noncycling human hematopoietic cells.
Proc Natl Acad Sci USA
87
1990
2770
150
John
S
Reeves
RB
Lin
JX
Child
R
Leiden
JM
Thompson
CB
Leonard
WJ
Regulation of cell-type-specific interleukin-2 receptor alpha-chain gene expression: Potential role of physical interactions between Elf-1, HMG-I(Y), and NF-kappa B family proteins.
Mol Cell Biol
15
1995
1786
151
Bassuk
AG
Leiden
JM
A direct physical association between ETS and AP-1 transcription factors in normal human T cells.
Immunity
3
1995
223
152
Gauthier
JM
Bourachot
B
Doucas
V
Yaniv
M
Moreau-Gachelin
F
Functional interference between the Spi-1/PU.1 oncoprotein and steroid hormone or vitamin receptors.
EMBO J
12
1993
5089
153
Marais
R
Wynne
J
Treisman
R
The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain.
Cell
73
1993
381
154
Rao
VN
Reddy
ESP
Elk-1 proteins are phosphoproteins and activators of mitogen-activated protein kinase.
Cancer Res
53
1993
3449
155
Rabault
B
Ghysdael
J
Calcium-induced phosphorylation of ETS1 inhibits its specific DNA binding activity.
J Biol Chem
269
1994
28143
156
Yang
BS
Hauser
CA
Henkel
G
Colman
MS
Van Beveren
C
Stacey
KJ
Hume
DA
Maki
RA
Ostrowski
MC
Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2.
Mol Cell Biol
16
1996
538
157
Mao
C
Ray-Gallet
D
Tavitian
A
Moreau-Gachelin
F
Differential phosphorylations of Spi-B and Spi-1 transcription factors.
Oncogene
12
1996
863
158
Lodie
TA
Savedra
R
Golenbaock
DT
Van Beveren
CP
Maki
RA
Fenton
MJ
Stimulation of macrophages by LPS alters the phosphorylation state, conformation, and function of PU.1 via activation of casein kinase II.
J Immunol
158
1997
1848
159
Celada
A
Borras
FE
Soler
C
Lloberas
J
Klemsz
M
Van Beveren
C
McKercher
SC
Maki
RA
The transcription factor PU.1 is involved in macrophage proliferation.
J Exp Med
184
1996
61
160
Ford
AM
Bennett
CA
Healy
LE
Towatari
M
Greaves
MF
Enver
T
Regulation of the myeloperoxidase enhancer binding proteins PU.1, CEBPα, β, and δ during granulocytic-lineage specification.
Proc Natl Acad Sci USA
93
1996
10838
161
McKercher
SR
Torbett
BE
Anderson
KL
Henkel
GW
Vestal
DJ
Baribault
H
Klemsz
M
Feeney
AJ
Wu
GE
Paige
CJ
Maki
RA
Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities.
EMBO J
15
1996
5647
162
Olson
MC
Scott
EW
Hack
AA
Su
GH
Tenen
DG
Singh
H
Simon
MC
PU.1 is not essential for early myeloid gene expression but is required for terminal myeloid differentiation.
Immunity
3
1995
703
163
Henkel
GW
McKercher
SR
Yamamoto
H
Anderson
KL
Oshima
RG
Maki
RA
PU.1 but not Ets-2 is essential for macrophage development from ES cells.
Blood
88
1996
2917
164
Reddy
MA
Yang
BS
Yue
X
Barnett
CJK
Ross
IL
Sweet
MJ
Hume
DA
Ostrowski
MC
Opposing actions of c-ets/PU.1 and c-myb protooncogene products in regulating the macrophage-specific promoters of the human and mouse colony-stimulating factor-1 receptor (c-fms) genes.
J Exp Med
180
1994
2309
165
Hallier
M
Tavitian
A
Moreau-Gachelin
F
The transcription factor Spi-1/PU.1 binds RNA and interferes with the RNA-binding protein p54(nrb).
J Biol Chem
271
1996
11177
166
Moulton
KS
Semple
K
Wu
H
Glass
CK
Cell-specific expression of the macrophage scavenger receptor gene is dependent on PU.1 and a composite AP-1/ets motif.
Mol Cell Biol
14
1994
4408
167
Kola
I
Brookes
S
Green
AR
Garber
R
Tymms
M
Papas
TS
Seth
A
The Ets1 transcription factor is widely expressed during murine embryo development and is associated with mesodermal cells involved in morphogenetic processes such as organ formation.
Proc Natl Acad Sci USA
90
1993
7588
168
Klemsz
MJ
Maki
RA
Papayannopoulou
T
Moore
J
Hromas
R
Characterization of the ets oncogene family member, fli-1.
J Biol Chem
268
1993
5769
169
Ross
IL
Dunn
TL
Yue
X
Roy
S
Barnett
CJK
Hume
DA
Comparison of the expression and function of the transcription factor PU.1 (Spi-1 proto-oncogene) between murine macrophages and B lymphocytes.
Oncogene
9
1994
121
170
Rosmarin
AG
Caprio
DG
Kirsch
DG
Handa
H
Simkevich
CP
GABP and PU.1 compete for binding, yet cooperate to increase CD18 (β2 leukocyte integrin) transcription.
J Biol Chem
270
1995
23627
171
Golub
TR
Barker
GF
Lovett
M
Gilliland
DG
Fusion of PDGF receptor beta to a novel ETS-like gene, Tel, in chronic myelomonocytic leukemia with t(5:12) chromosomal translocation.
Cell
77
1994
307
172
Golub
TR
Barker
GF
Bohlander
SK
Hiebert
SW
Ward
DC
Brayward
P
Morgan
E
Raimondi
SC
Rowley
JD
Gilliland
DG
Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia.
Proc Natl Acad Sci USA
92
1995
4917
173
Golub TR, Mclean T, Stegmaier K, Carroll M, Tomasson M, Gilliland DG: The TEL gene and human leukemia. Bba-Rev Cancer 1288:M7, 1996
174
Johnson
PF
Landschulz
WH
Graves
BJ
McKnight
SL
Identification of a rat liver nuclear protein that binds to the enhancer core element of three animal viruses.
Genes Dev
1
1987
133
175
Landschulz
WH
Johnson
PF
Adashi
EY
Graves
BJ
McKnight
SL
Isolation of a recombinant copy of the gene encoding C/EBP.
Genes Dev
2
1988
786
176
Landschulz
WH
Johnson
PF
McKnight
SL
The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite.
Science
243
1989
1681
177
Johnson
PF
McKnight
SL
Eukaryotic transcriptional regulatory proteins.
Annu Rev Biochem
58
1989
799
178
Vallejo
M
Ron
D
Miller
CP
Habener
JF
C/ATF, a member of the activating transcription factor family of DNA-binding proteins, dimerizes with CAAT/enhancer-binding proteins and directs their binding to cAMP response elements.
Proc Natl Acad Sci USA
90
1993
4679
179
Cao
Z
Umek
RM
McKnight
SL
Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells.
Genes Dev
5
1991
1538
180
Lin
FT
Lane
MD
CCAAT/enhancer binding protein α is sufficient to initiate the 3T3-L1 adipocyte differentiation program.
Proc Natl Acad Sci USA
91
1994
8757
181
Hendricks-Taylor
LR
Darlington
GJ
Inhibition of cell proliferation by C/EBP alpha occurs in many cell types, does not require the presence of p53 or Rb, and is not affected by large T-antigen.
Nucleic Acids Res
23
1995
4726
182
Watkins
PJ
Condreay
JP
Huber
BE
Jacobs
SJ
Adams
DJ
Impaired proliferation and tumorigenicity induced by CCAAT/enhancer-binding protein.
Cancer Res
56
1996
1063
183
Timchenko
NA
Wilde
M
Nakanishi
M
Smith
JR
Darlington
GJ
CCAAT/enhancer-binding protein α (C/EBPα) inhibits cell proliferation though the p21 (WAF-1/CIP-1/SDI-1) protein.
Genes Dev
10
1996
804
184
Williams
SC
Cantwell
CA
Johnson
PF
A family of C/EBP-related proteins capable of forming covalently linked leucine zipper dimers in vitro.
Genes Dev
5
1991
1553
185
Akira
S
Isshiki
H
Sugita
T
Tanabe
O
Kinoshita
S
Nishio
Y
Nakajima
T
Hirano
T
Kishimoto
T
A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family.
EMBO J
9
1990
1897
186
Chumakov
AM
Griller
I
Chumakova
E
Chih
D
Slater
J
Koeffler
HP
Cloning of the novel human myeloid-cell-specific C/EBP-epsilon transcription factor.
Mol Cell Biol
17
1997
1375
187
Antonson
P
Stellan
B
Yamanaka
R
Xanthopoulos
KG
A novel human CCAAT/enhancer binding protein gene, C/EBPε, is expressed in cells of lymphoid and myeloid lineages and is localized on chromsome 14q11.2 close to the T-cell receptor α/δ locus.
Genomics
35
1996
30
188
Descombes
P
Schibler
U
A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA.
Cell
67
1991
569
189
Ossipow
V
Descombes
P
Schibler
U
CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials.
Proc Natl Acad Sci USA
90
1993
8219
190
Ron
D
Habener
JF
CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription.
Genes Dev
6
1992
439
191
Friedman
AD
GADD153/CHOP, a DNA damage-inducible protein, reduced CAAT/enhancer binding protein activities and increased apoptosis in 32D c13 myeloid cells.
Cancer Res
56
1996
3250
192
Christy
RJ
Kaestner
KH
Geiman
DE
Lane
MD
CCAAT/enhancer binding protein gene promoter: Binding of nuclear factors during differentiation of 3T3-L1 preadipocytes.
Proc Natl Acad Sci USA
88
1991
2593
193
Li
LH
Nerlov
C
Prendergast
G
MacGregor
D
Ziff
EB
c-Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II.
EMBO J
13
1994
4070
194
Timchenko
N
Wilson
DR
Taylor
LR
Abdelsayed
S
Wilde
M
Sawadogo
M
Darlington
GJ
Autoregulation of the human C/EBP alpha gene by stimulation of upstream stimulatory factor binding.
Mol Cell Biol
15
1995
1192
195
Scott
LM
Civin
CI
Rorth
P
Friedman
AD
A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells.
Blood
80
1992
1725
196
Katz
S
Kowenzleutz
E
Muller
C
Meese
K
Ness
SA
Leutz
A
The NF-M transcription factor is related to C/EBP-beta and plays a role in signal transduction, differentiation and leukemogenesis of avian myelomonocytic cells.
EMBO J
12
1993
1321
197
Ness
SA
Kowenzleutz
E
Casini
T
Graf
T
Leutz
A
Myb and NF-M — Combinatorial activators of myeloid genes in heterologous cell types.
Genes Dev
7
1993
749
198
Sterneck
E
Muller
C
Katz
S
Leutz
A
Autocrine growth induced by kinase type oncogenes in myeloid cells requires AP-1 and NF-M, a myeloid specific, C/EBP-like factor.
EMBO J
11
1992
115
199
Haas
JG
Strobel
M
Leutz
A
Wendelgass
P
Muller
C
Sterneck
E
Riethmuller
G
Ziegler-Heitbrock
HW
Constitutive monocyte-restricted activity of NF-M, a nuclear factor that binds to a C/EBP motif.
J Immunol
149
1992
237
200
Natsuka
S
Akira
S
Nishio
Y
Hashimoto
S
Sugita
T
Isshiki
H
Kishimoto
T
Macrophage differentiation-specific expression of NF-IL6, a transcription factor for interleukin-6.
Blood
79
1992
460
201
Landschulz
WH
Johnson
PF
McKnight
SL
The leucine zipper: A hypothetical structure common to a new class of DNA binding proteins.
Science
240
1988
1759
202
Williams
SC
Baer
M
Dillner
AJ
Johnson
PF
CRP2 (C/EBP beta) contains a bipartite regulatory domain that controls transcriptional activation, DNA binding and cell specificity.
EMBO J
14
1995
3170
203
Friedman
AD
McKnight
SL
Identification of two polypeptide segments of CCAAT/enhancer-binding protein required for transcriptional activation of the serum albumin gene.
Genes Dev
4
1990
1416
204
Jones
KA
Kadonaga
JT
Rosenfeld
PJ
Kelly
TJ
Tjian
R
A cellular DNA-binding protein that activates eukaryotic transcription and DNA replication.
Cell
48
1987
79
205
Dorn
A
Bollekens
J
Staub
A
Benoist
C
Mathis
D
A multiplicity of CCAAT box-binding proteins.
Cell
50
1987
863
206
van Huijsduijnen
RH
Li
XY
Black
D
Matthes
H
Benoist
C
Mathis
D
Co-evolution from yeast to mouse: cDNA cloning of the two NF-Y (CP- 1/CBF) subunits.
EMBO J
9
1990
3119
207
Maity
SN
Sinha
S
Ruteshouser
EC
de Crombrugghe
B
Three different polypeptides are necessary for DNA binding of the mammalian heteromeric CCAAT binding factor.
J Biol Chem
267
1992
16574
208
Pope
RM
Leutz
A
Ness
SA
C/EBP beta regulation of the tumor necrosis factor alpha gene.
J Clin Invest
94
1994
1449
209
Osada
S
Yamamoto
H
Nishihara
T
Imagawa
M
DNA binding specificity of the CCAAT/enhancer-binding protein transcription factor family.
J Biol Chem
271
1996
3891
210
Stein
B
Cogswell
PC
Baldwin
AS Jr
Functional and physical associations between NF-kB and C/EBP family members: A Rel domain-bZIP interaction.
Mol Cell Biol
13
1993
3964
211
Diehl
JA
Hannink
M
Identification of a C/EBP-Rel complex in avian lymphoid cells.
Mol Cell Biol
14
1994
6635
212
Lee
YH
Yano
M
Liu
SY
Matsunaga
E
Johnson
PF
Gonzalez
FJ
A novel cis-acting element controlling the rat CYP2D5 gene and requiring cooperativity between C/EBP beta and an Sp1 factor.
Mol Cell Biol
14
1994
1383
213
Chen
PL
Riley
DJ
Chen-Kiang
S
Lee
WH
Retinoblastoma protein directly interacts with and activates the transcription factor NF-IL6.
Proc Natl Acad Sci USA
93
1995
465
214
Hsu
W
Kerppola
TK
Chen
P
Curran
T
Chen-Kiang
S
Fos and jun repress transcription activation by NF-IL6 through association at the basic zipper region.
Mol Cell Biol
14
1993
268
215
Zhang
D-E
Hetherington
CJ
Meyers
S
Rhoades
KL
Larson
CJ
Chen
HM
Hiebert
SW
Tenen
DG
CCAAT enhancer binding protein (C/EBP) and AML1 (CBFα2) synergistically activate the M-CSF receptor promoter.
Mol Cell Biol
16
1996
1231
216
Chen
PL
Riley
DJ
Chen
YM
Lee
WH
Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs.
Gene Dev
10
1996
2794
217
Wang
ND
Finegold
MJ
Bradley
A
Ou
CN
Abdelsayed
SV
Wilde
MD
Taylor
LR
Wilson
DR
Darlington
GJ
Impaired energy homeostasis in C/EBPα knockout mice.
Science
269
1995
1108
218
Flodby
P
Barlow
C
Kylefjord
H
Ahrlund-Richter
L
Xanthopoulos
KG
Increased hepatic cell proliferation and lung abnormalities in mice deficient in CCAAT/enhancer binding protein α.
J Biol Chem
271
1996
24753
219
Lui
F
Wu
HY
Wesselschmidt
RL
Kornaga
T
Link
DC
Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice.
Immunity
5
1996
491
220
Metz
R
Ziff
E
cAMP stimulates the C/EBP-related transcription factor NFIL-6 to trans-locate to the nucleus and induce c-fos transcription.
Genes Dev
5
1991
1754
221
Wegner
M
Cao
Z
Rosenfeld
MG
Calcium-regulated phosphorylation within the leucine zipper of C/EBP beta.
Science
256
1992
370
222
Tanaka
T
Akira
S
Yoshida
K
Umemoto
M
Yoneda
Y
Shirafuji
N
Fujiwara
H
Suematsu
S
Yoshida
N
Kishimoto
T
Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macroophages.
Cell
80
1995
353
223
Screpanti
I
Romani
L
Musiani
P
Modesti
A
Fattori
E
Lazzaro
D
Sellitto
C
Scarpa
S
Bellavia
D
Lattanzio
G
Bistoni
F
Frati
L
Cortese
R
Gulino
A
Ciliberto
G
Costantini
F
Poli
V
Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice.
EMBO J
14
1995
1932
224
Akira
S
Yoshida
K
Tanaka
T
Taga
T
Kishimoto
T
Targeted disruption of the IL-6 related genes: gp130 and NF-IL-6.
Immunol Rev
148
1995
221
225
Crozat
A
Aman
P
Mandahl
N
Ron
D
Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.
Nature
363
1993
640
226
Hendricks-Taylor
LR
Bachinski
LL
Siciliano
MJ
Fertitta
A
Trask
B
de Jong
PJ
Ledbetter
DH
Darlington
GJ
The CCAAT/enhancer binding protein (C/EBP alpha) gene (CEBPA) maps to human chromosome 19q13.1 and the related nuclear factor NF-IL6 (C/EBP beta) gene (CEBPB) gene maps to human chrosome 20q13.1.
Genomics
14
1992
12
227
Barberis
A
Superti-Furga
G
Busslinger
M
Mutually exclusive interaction of the CCAAT-binding factor and of a displacement protein with overlapping sequences of a histone gene promoter.
Cell
50
1987
347
228
Skalnik
DG
Strauss
EC
Orkin
SH
CCAAT displacement protein as a repressor of the myelomonocytic-specific gp91-phox gene promoter.
J Biol Chem
266
1991
16736
229
Neufeld
EJ
Skalnik
DG
Lievens
PM
Orkin
SH
Human CCAAT displacement protein is homologous to the Drosophila homeoprotein, cut.
Nat Genet
1
1992
50
230
Khanna-Gupta A, Zibello T, Neufeld E, Berliner N: CCAAT displacement protein (CDP) recognizes a silencer element within the lactoferrin gene promoter. Blood (submitted)
231
He
GP
Mulse
A
Li
AW
Ro
HS
A eukaryotic transcriptional repressor with carboxypeptidase activity.
Nature
378
1995
92
232
Wang
S
Wang
Q
Crute
BE
Melnikova
IN
Keller
SR
Speck
NA
Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor.
Mol Cell Biol
13
1993
3324
233
Ogawa
E
Maruyama
M
Kagoshima
H
Inuzuka
M
Lu
J
Satake
M
Shigesada
K
Ito
Y
PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila Runt gene and the human AML1 gene.
Proc Natl Acad Sci USA
90
1993
6859
234
Levanon
D
Negreanu
V
Bernstein
Y
Baram
I
Avivi
L
Groner
Y
AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression, and chromosomal localization.
Genomics
23
1994
425
235
Tanaka
T
Tanaka
K
Ogawa
S
Kurokawa
M
Mitani
K
Nishida
J
Shibata
Y
Yazaki
Y
Hirai
H
An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms.
EMBO J
14
1995
341
236
Takahashi
A
Satake
M
Yamaguchiiwai
Y
Bae
SC
Lu
J
Maruyama
M
Zhang
YW
Oka
H
Arai
N
Arai
K
Ito
Y
Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1- related transcription factor, PEBP2.
Blood
86
1995
607
237
Miyoshi
H
Ohira
M
Shimizu
K
Mitani
K
Hirai
H
Imai
T
Yokoyama
K
Soeda
E
Ohki
M
Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia.
Nucleic Acids Res
23
1995
2762
238
Meyers
S
Lenny
N
Hiebert
SW
The t(8:21) fusion protein interferes with AML-1B-dependent transcriptional activation.
Mol Cell Biol
15
1995
1974
239
Kagoshima
H
Shigesada
K
Satake
M
Ito
Y
Miyoshi
H
Ohki
M
Pepling
M
Gergen
P
The Runt domain identifies a new family of heteromeric transcriptional regulators.
Trends Genet
9
1993
338
240
Kania
MA
Bonner
AS
Duffy
JB
Gergen
JP
The Drosophila segmentation gene runt encodes a novel nuclear regulatory protein that is also expressed in the developing nervous system.
Genes Dev
4
1990
1701
241
Meyers
S
Downing
JR
Hiebert
SW
Identification of AML-1 and the (8; 21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins — The Runt homology domain is required for DNA binding and protein-protein interactions.
Mol Cell Biol
13
1993
6336
242
Tanaka
K
Tanaka
T
Ogawa
S
Kurokawa
M
Mitani
K
Yazaki
Y
Hirai
H
Increased expression of AML1 during retinoic-acid-induced differentiation of U937 cells.
Biochem Biophys Res Commun
211
1995
1023
243
Zhu
X
Yeadon
JE
Burden
SJ
AML1 is expressed in skeletal muscle and is regulated by innervation.
Mol Cell Biol
14
1994
8051
244
Wang
Q
Stacy
T
Miller
JD
Lewis
AF
Gu
T-L
Huang
X
Bushweller
JH
Bories
JC
Alt
FW
Ryan
G
Liu
PP
Wynshaw-Boris
A
Binder
M
Marin-Padilla
M
Sharpe
AH
Speck
NA
The CBF β subunit is essential for CBFα2 (AML1) function in vivo.
Cell
87
1996
697
245
Zhang
D-E
Hohaus
S
Voso
MT
Chen
HM
Smith
LT
Hetherington
CJ
Tenen
DG
Function of PU.1 (Spi-1), C/EBP, and AML1 in early myelopoiesis: Regulation of multiple myeloid CSF receptor promoters.
Curr Top Microbiol Immunol
211
1996
137
246
Giese
K
Kingsley
C
Kirshner
JR
Grosschedl
R
Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions.
Genes Dev
9
1995
995
247
Hernandez-Munain
C
Krangel
MS
Regulation of the T-cell receptor delta enhancer by functional cooperation between c-Myb and core-binding factors.
Mol Cell Biol
14
1994
473
248
Wotton
D
Ghysdael
J
Wang
S
Speck
NA
Owen
MJ
Cooperative binding of Ets-1 and core binding factor to DNA.
Mol Cell Biol
14
1994
840
249
Sun
WW
Graves
BJ
Speck
NA
Transactivation of the Moloney murine leukemia virus and T-cell receptor beta-chain enhancers by cbf and ets requires intact binding sites for both proteins.
J Virol
69
1995
4941
250
Tanaka
T
Kurokawa
M
Ueki
K
Tanaka
K
Imai
Y
Mitani
K
Okazaki
K
Sagata
N
Yazaki
Y
Shibata
Y
Kadowaki
T
Hirai
H
The extracellular signal-regulated kinase pathway phosphorylates AML1, an acute myeloid leukemia gene product, and potentially regulates its transactivation ability.
Mol Cell Biol
16
1996
3967
251
Miyoshi
H
Kozu
T
Shimizu
K
Enomoto
K
Maseki
N
Kaneko
Y
Kamada
N
Ohki
M
The t(8-21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript.
EMBO J
12
1993
2715
252
Erickson
P
Gao
J
Chang
KS
Look
T
Whisenant
E
Raimondi
S
Lasher
R
Trujillo
J
Rowley
J
Drabkin
H
Identification of breakpoints in t(8; 21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt.
Blood
80
1992
1825
253
Mitani
K
Ogawa
S
Tanaka
T
Miyoshi
H
Kurokawa
M
Mano
H
Yazaki
Y
Ohki
M
Hirai
H
Generation of the AML1-EVI-1 fusion gene in the t(3; 21)(q26; q22) causes blastic crisis in chronic myelocytic leukemia.
EMBO J
13
1994
504
254
Nucifora
G
Begy
CR
Erickson
P
Drabkin
HA
Rowley
JD
The 3; 21 translocation in myelodysplasia results in a fusion transcript between the AML1 gene and the gene for EAP, a highly conserved protein associated with the Epstein-Barr virus small RNA EBER-1.
Proc Natl Acad Sci USA
90
1993
7784
255
Romana
SP
Mauchauffe
M
Le Coniat
M
Chumakov
I
Le Paslier
D
Berger
R
Bernard
OA
The t(12; 21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion.
Blood
85
1995
3662
256
Nucifora
G
Birn
DJ
Espinosa
R
Erickson
P
LeBeau
MM
Roulston
D
McKeithan
TW
Drabkin
H
Rowley
JD
Involvement of the AML1 gene in the t(3; 21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis.
Blood
81
1993
2728
257
Liu
P
Tarle
SA
Hajra
A
Claxton
DF
Marlton
P
Freedman
M
Siciliano
MJ
Collins
FS
Fusion between transcription factor CBF-beta/PEBP2-beta and a myosin heavy chain in acute myeloid leukemia.
Science
261
1993
1041
258
Frank
R
Zhang
J
Uchida
H
Meyers
S
Hiebert
SW
Nimer
SD
The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B.
Oncogene
11
1995
2667
259
Hiebert
SW
Sun
W
Davis
JN
Golub
T
Shurtleff
S
Buijs
A
Downing
JR
Grosveld
G
Roussell
MF
Gilliland
DG
Lenny
N
Meyers
S
The t(12; 21) translocation converts AML-1B from an activator to a repressor of transcription.
Mol Cell Biol
16
1996
1349
260
Taylor
DS
Laubach
JP
Nathan
DG
Mathey-Prevot
B
Cooperation between core binding factor and adjacent promoter elements contributes to the tissue-specific expression of interleukin-3.
J Biol Chem
271
1996
14020
261
Uchida
H
Zhang
J
Nimer
SD
AML1A and AML1B can transactivate the human IL-3 promoter.
J Immunol
158
1997
2251
262
Friedman
AD
Britosbray
M
Suzow
J
The murine myeloperoxidase gene contains a bipartite distal enhancer, including a novel region regulated by PEBP2/CBF.
Leuk Res
20
1996
809
263
Rhoades
KL
Hetherington
CJ
Rowley
JD
Hiebert
SW
Nucifora
G
Tenen
DG
Zhang
D-E
Synergistic up-regulation of the myeloid-specific promoter for the macrophage colony-stimulating factor receptor by AML1 and the t(8; 21) fusion protein may contribute to leukemogenesis.
Proc Natl Acad Sci USA
93
1996
11895
264
Matsushime
H
Roussel
MF
Ashmun
RA
Sherr
CJ
Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle.
Cell
65
1991
701
265
Borycki
AG
Foucrier
J
Saffar
L
Leibovitch
SA
Repression of the CSF-1 receptor (c-fms proto-oncogene product) by antisense transfection induces G1-growth arrest in L6 alpha 1 rat myoblasts.
Oncogene
10
1995
1799
266
Sherr
CJ
Rettenmier
CW
Sacca
R
Roussel
MF
Look
AT
Stanley
ER
The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1.
Cell
41
1985
665
267
Roussel
MF
Dull
TJ
Rettenmier
CW
Ralph
P
Ullrich
A
Sherr
CJ
Transforming potential of the c-fms proto-oncogene (CSF-1 receptor).
Nature
325
1987
549
268
Gisselbrecht
S
Fichelson
S
Sola
B
Bordereaux
D
Hampe
A
Andre
C
Galibert
F
Tambourin
P
Frequent c-fms activation by proviral insertion in mouse myeloblastic leukaemias.
Nature
329
1987
259
269
Yergeau
DA
Hetherington
CJ
Wang
Q
Zhang
P
Sharpe
AH
Binder
M
Marin-Padilla
M
Tenen
DG
Speck
NA
Zhang
D-E
Embryonic lethality and impairment of hemtopoiesis in mice heterozygous for an AML1-ETO fusion gene.
Nat Genet
15
1997
303
270
Castilla
LH
Wijmenga
C
Wang
Q
Stacy
T
Speck
NA
Eckhaus
M
Marin-Padilla
M
Collins
FS
Wynshaw-Boris
A
Liu
PP
Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFβ-MYH11.
Cell
87
1996
687
271
Hodges
RE
Sauberlich
HE
Canham
JE
Wallace
DL
Rucker
RB
Mejia
LA
Mohanram
M
Hematopoietic studies in vitamin A deficiency.
Am J Clin Nutr
31
1978
876
272
Douer
D
Koeffler
HP
Retinoic acid enhances colony-stimulating factor-induced clonal growth of normal human myeloid progenitor cells in vitro.
Exp Cell Res
138
1982
193
273
Gratas
C
Menot
ML
Dresch
C
Chomienne
C
Retinoid acid supports granulocytic but not erythroid differentiation of myeloid progenitors in normal bone marrow cells.
Leukemia
7
1993
1156
274
Breitman
TR
Selonick
SE
Collins
SJ
Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid.
Proc Natl Acad Sci USA
77
1980
2936
275
Breitman
TR
Collins
SJ
Keene
BR
Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid.
Blood
57
1981
1000
276
Mangelsdorf
DJ
Evans
RM
The RXR heterodimers and orphan receptors.
Cell
83
1995
841
277
Evans
RM
The steroid and thyroid hormone receptor superfamily.
Science
240
1988
889
278
Glass
CK
DiRenzo
J
Kurokawa
R
Han
ZH
Regulation of gene expression by retinoic acid receptors.
DNA Cell Biol
10
1991
623
279
de The
H
Marchio
A
Tiollais
P
Dejean
A
Differential expression and ligand regulation of the retinoic acid receptor alpha and beta genes.
EMBO J
8
1989
429
280
Gallagher
RE
Said
F
Pua
I
Papenhausen
PR
Paietta
E
Wiernik
PH
Expression of retinoic acid receptor-alpha mRNA in human leukemia cells with variable responsiveness to retinoic acid.
Leukemia
3
1989
789
281
Largman
C
Detmer
K
Corral
JC
Hack
FM
Lawrence
HJ
Expression of retinoic acid receptor alpha mRNA in human leukemia cells.
Blood
74
1989
99
282
Umesono
K
Murakami
KK
Thompson
CC
Evans
RM
Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors.
Cell
65
1991
1255
283
Naar
AM
Boutin
JM
Lipkin
SM
Yu
VC
Holloway
JM
Glass
CK
Rosenfeld
MG
The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors.
Cell
65
1991
1267
284
Gudas
LJ
Retinoids and vertebrate development.
J Biol Chem
269
1994
15399
285
Mangelsdorf
DJ
Borgmeyer
U
Heyman
RA
Zhou
JY
Ong
ES
Oro
AE
Kakizuka
A
Evans
RM
Characterization of three RXR genes that mediate the action of 9-cis retinoic acid.
Genes Dev
6
1992
329
286
Collins
SJ
Robertson
KA
Mueller
L
Retinoic acid-induced granulocytic differentiation of HL-60 myeloid leukemia cells is mediated directly through the retinoic acid receptor (RAR-alpha).
Mol Cell Biol
10
1990
2154
287
Robertson
KA
Emami
B
Collins
SJ
Retinoic acid-resistant HL-60R cells harbor a point mutation in the retinoic acid receptor ligand-binding domain that confers dominant negative activity.
Blood
80
1992
1885
288
Robertson
KA
Emami
B
Mueller
L
Collins
SJ
Multiple members of the retinoic acid receptor family are capable of mediating the granulocytic differentiation of HL-60 cells.
Mol Cell Biol
12
1992
3743
289
Tsai
S
Bartelmez
S
Heyman
R
Damm
K
Evans
R
Collins
SJ
A mutated retinoic acid receptor-alpha exhibiting dominant-negative activity alters the lineage development of a multipotent hematopoietic cell line.
Genes Dev
6
1992
2258
290
Warrell
RP Jr
de The
H
Wang
ZY
Degos
L
Acute promyelocytic leukemia.
N Engl J Med
329
1993
177
291
de The
H
Chomienne
C
Lanotte
M
Degos
L
Dejean
A
The t(15; 17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus.
Nature
347
1990
558
292
Chang
KS
Stass
SA
Chu
DT
Deaven
LL
Trujillo
JM
Freireich
EJ
Characterization of a fusion cDNA (RARA/myl) transcribed from the t(15; 17) translocation breakpoint in acute promyelocytic leukemia.
Mol Cell Biol
12
1992
800
293
Goddard
AD
Borrow
J
Freemont
PS
Solomon
E
Characterization of a zinc finger gene disrupted by the t(15; 17) in acute promyelocytic leukemia.
Science
254
1991
1371
294
Kakizuka
A
Miller
WH Jr
Umesono
K
Warrell
RP Jr
Frankel
SR
Murty
VV
Dmitrovsky
E
Evans
RM
Chromosomal translocation t(15; 17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML.
Cell
66
1991
663
295
Alcalay
M
Zangrilli
D
Pandolfi
PP
Longo
L
Mencarelli
A
Giacomucci
A
Rocchi
M
Biondi
A
Rambaldi
A
Lo
Coco F
Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus.
Proc Natl Acad Sci USA
88
1991
1977
296
Pandolfi
PP
Grignani
F
Alcalay
M
Mencarelli
A
Biondi
A
LoCoco
F
Pelicci
PG
Structure and origin of the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoid-binding and transactivation properties.
Oncogene
6
1991
1285
297
Perez
A
Kastner
P
Sethi
S
Lutz
Y
Reibel
C
Chambon
P
PMLRAR homodimers — Distinct DNA binding properties and heteromeric interactions with RXR.
EMBO J
12
1993
3171
298
de The
H
Lavau
C
Marchio
A
Chomienne
C
Degos
L
Dejean
A
The PML-RAR alpha fusion mRNA generated by the t(15; 17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR.
Cell
66
1991
675
299
Chen
Z
Brand
NJ
Chen
A
Chen
SJ
Tong
JH
Wang
ZY
Waxman
S
Zelent
A
Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11; 17) translocation associated with acute promyelocytic leukaemia.
EMBO J
12
1993
1161
300
Redner
RL
Rush
EA
Faas
S
Rudert
WA
Corey
SJ
The t(5; 17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion.
Blood
87
1996
882
301
Guidez
F
Huang
W
Tong
JH
Dubois
C
Balitrand
N
Waxman
S
Michaux
JL
Martiat
P
Degos
L
Chen
Z
Waxman
S
Chomienne
C
Poor response to all-trans retinoic acid therapy in a t(11; 17) PLZF/RAR alpha patient.
Leukemia
8
1994
312
302
Licht
JD
Chomienne
C
Goy
A
Chen
A
Scott
AA
Head
DR
Michaux
JL
Wu
Y
DeBlasio
A
Miller
WH Jr
Zelenetz
AD
Willman
CL
Chen
Z
Chen
S-J
Zelent
A
Macintyre
E
Veil
A
Cortes
J
Kantarjian
H
Waxman
S
Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11; 17).
Blood
85
1995
1083
303
Rousselot
P
Hardas
B
Patel
A
Guidez
F
Gaken
J
Castaigne
S
Dejean
A
Dethe
H
Degos
L
Farzaneh
F
Chomienne
C
The PML-Rar alpha gene product of the t(1517) translocation inhibits retinoic acid-induced granulocytic differentiation and mediated transactivation in human myeloid cells.
Oncogene
9
1994
545
304
Grignani
F
Ferrucci
PF
Testa
U
Talamo
G
Fagioli
M
Alcalay
M
Mencarelli
A
Peschle
C
Nicoletti
I
Pelicci
PG
The acute promyelocytic leukemia-specific PML-RAR-alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells.
Cell
74
1993
423
305
Chomienne
C
Balitrand
N
Ballerini
P
Castaigne
S
de The
H
Degos
L
All-trans retinoic acid modulates the retinoic acid receptor-alpha in promyelocytic cells.
J Clin Invest
88
1991
2150
306
Leroy
P
Nakshatri
H
Chambon
P
Mouse retinoic acid receptor alpha 2 isoform is transcribed from a promoter that contains a retinoic acid response element.
Proc Natl Acad Sci USA
88
1991
10138
307
Liu
M
Iavarone
A
Freedman
LP
Transcriptional activation of the human p21(WAF1/CIP1) gene by retinoic acid receptor — Correlation with retinoid induction of U937 cell differentiation.
J Biol Chem
271
1996
31723
308
Lawrence
HJ
Largman
C
Homeobox genes in normal hematopoiesis and leukemia.
Blood
80
1992
2445
309
Lowney
P
Corral
J
Detmer
K
LeBeau
MM
Deaven
L
Lawrence
HJ
Largman
C
A human Hox 1 homeobox gene exhibits myeloid-specific expression of alternative transcripts in human hematopoietic cells.
Nucleic Acids Res
19
1991
3443
310
Shen
WF
Largman
C
Lowney
P
Corral
JC
Detmer
K
Hauser
CA
Simonitch
TA
Hack
FM
Lawrence
HJ
Lineage-restricted expression of homeobox-containing genes in human hematopoietic cell lines.
Proc Natl Acad Sci USA
86
1989
8536
311
Magli
MC
Barba
P
Celetti
A
De Vita
G
Cillo
C
Boncinelli
E
Coordinate regulation of HOX genes in human hematopoietic cells.
Proc Natl Acad Sci USA
88
1991
6348
312
Shen
WF
Detmer
K
Mathews
CH
Hack
FM
Morgan
DA
Largman
C
Lawrence
HJ
Modulation of homeobox gene expression alters the phenotype of human hematopoietic cell lines.
EMBO J
11
1992
983
313
Lawrence
HJ
Sauvageau
G
Humphries
RK
Largman
C
The role of HOX homeobox genes in normal and leukemic hematopoiesis.
Stem Cells
14
1996
281
314
Boylan
JF
Lufkin
T
Achkar
CC
Taneja
R
Chambon
P
Gudas
LJ
Targeted disruption of retinoic acid receptor alpha (RAR alpha) and RAR gamma results in receptor-specific alterations in retinoic acid-mediated differentiation and retinoic acid metabolism.
Mol Cell Biol
15
1995
843
315
Liu
M
Lee
MH
Cohen
M
Bommakanti
M
Freedman
LP
Transcriptional activation of the Cdk inhibitor p21 by vitamin D-3 leads to the induced differentiation of the myelomonocytic cell line U937.
Genes Dev
10
1996
142
316
Burn
TC
Petrovick
MS
Hohaus
S
Rollins
BJ
Tenen
DG
Monocyte chemoattractant protein-1 gene is expressed in activated neutrophils and retinoic acid-induced human myeloid cell lines.
Blood
84
1994
2776
317
Kastner
P
Mark
M
Chambon
P
Nonsteroid nuclear receptors: What are genetic studies telling us about their role in real life?
Cell
83
1995
859
318
Kastner
P
Grondona
JM
Mark
M
Gansmuller
A
Lemeur
M
Decimo
D
Vonesch
JL
Dolle
P
Chambon
P
Genetic analysis of RXR alpha, developmental function: Convergence of RXR and RAR signaling pathways in heart and eye morphogenesis.
Cell
78
1994
987
319
Lohnes
D
Mark
M
Mendelsohn
C
Dolle
P
Dierich
A
Gorry
P
Gansmuller
A
Chambon
P
Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants.
Development
120
1994
2723
320
Mendelsohn
C
Lohnes
D
Decimo
D
Lufkin
T
Lemeur
M
Chambon
P
Mark
M
Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants.
Development
120
1994
2749
321
Klug
A
Rhodes
D
Zinc fingers: A novel protein fold for nucleic acid recognition.
Cold Spring Harb Symp Quant Biol
52
1987
473
322
Bogaert
T
Brown
N
Wilcox
M
The Drosophila PS2 antigen is an invertebrate integrin that, like the fibronectin receptor, becomes localized to muscle attachments.
Cell
51
1987
929
323
Sukhatme
VP
The Egr transcription factor family: From signal transduction to kidney differentiation.
Kidney Int
41
1992
550
324
Gessler
M
Poustka
A
Cavenee
W
Neve
RL
Orkin
SH
Bruns
GA
Homozygous deletion in Wilms' tumours of a zinc-finger gene identified by chromosome jumping.
Nature
343
1990
774
325
Call
KM
Glaser
T
Ito
CY
Buckler
AJ
Pelletier
J
Haber
DA
Rose
EA
Kral
A
Yeger
H
Lewis
WH
Jones
C
Housman
DE
Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus.
Cell
60
1990
509
326
Gabig
TG
Mantel
PL
Rosli
R
Crean
CD
Requiem: A novel zinc finger gene essential for apoptosis in myeloid cells.
J Biol Chem
269
1994
29515
327
Morishita
K
Parker
DS
Mucenski
ML
Jenkins
NA
Copeland
NG
Ihle
JN
Retroviral activation of a novel gene encoding a zinc finger protein in IL-3-dependent myeloid leukemia cell lines.
Cell
54
1988
831
328
Sacchi
N
Nisson
PE
Watkins
PC
Faustinella
F
Wijsman
J
Hagemeijer
A
AMLI fusion transcripts in t(3; 21) positive leukemia: Evidence of molecular heterogeneity and usage of splicing sites frequently involved in the generation of normal AMLI transcripts.
Gene Chromosome Cancer
11
1994
226
329
Tanaka
T
Mitani
K
Kurokawa
M
Ogawa
S
Tanaka
K
Nishida
J
Yazaki
Y
Shibata
Y
Hirai
H
Dual functions of the AML1/Evi-1 chimeric protein in the mechanism of leukemogenesis in t(3; 21) leukemias.
Mol Cell Biol
15
1995
2383
330
Chen
ZX
Xue
YQ
Zhang
R
Tao
RF
Xia
XM
Li
C
Wang
W
Zu
WY
Yao
XZ
Ling
BJ
A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients.
Blood
78
1991
1413
331
Reid
A
Gould
A
Brand
N
Cook
M
Strutt
P
Li
J
Licht
J
Waxman
S
Krumlauf
R
Zelent
A
Leukemia translocation gene, PLZF, is expressed with a speckled nuclear pattern in early hematopoietic progenitors.
Blood
86
1995
4544
332
Licht
JD
Shaknovich
R
English
MA
Melnick
A
Li
JY
Reddy
JC
Dong
S
Chen
SJ
Zelent
A
Waxman
S
Reduced and altered DNA-binding and transcriptional properties of the PLZF-retinoic acid receptor-alpha chimera generated in t(11; 17)-associated acute promyelocytic leukemia.
Oncogene
12
1996
323
333
Dyck
JA
Maul
GG
Miller
WH
Chen
JD
Kakizuka
A
Evans
RM
A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoproteinn.
Cell
76
1994
333
334
Weis
K
Rambaud
S
Lavau
C
Jansen
J
Carvalho
T
Carmofonseca
M
Lamond
A
Dejean
A
Retinoic acid regulates aberrant nuclear localization of PML-RAR alpha in acute promyelocytic leukemia cells.
Cell
76
1994
345
335
Koken
MH
Puvion-Dutilleul
F
Guillemin
MC
Viron
A
Linares-Cruz
G
Stuurman
N
de Jong
L
Szostecki
C
Calvo
F
Chomienne
C
Degos
L
Pavion
E
de The
H
The t(15; 17) translocation alters a nuclear body in a retinoic acid-reversible fashion.
EMBO J
13
1994
1073
336
Li JY, English MA, Bischt S, Waxman S, Licht JD: DNA binding and transcriptional regulation by the promyelocytic zinc finger protein. Blood 84:41a, 1994 (abstr, suppl 1)
337
Bardwell
VJ
Treisman
R
The POZ domain: A conserved protein-protein interaction motif.
Genes Dev
8
1994
1664
338
Albagli
O
Dhordain
P
Deweindt
C
Lecocq
G
Leprince
D
The BTB/POZ domain: A new protein-protein interaction motif common to DNA- and actin-binding proteins.
Cell Growth Differ
6
1995
1193
339
Dong
S
Zhu
J
Reid
A
Strutt
P
Guidez
F
Zhong
HJ
Wang
ZY
Licht
J
Waxman
S
Chomienne
C
Chen
Z
Zelent
A
Chen
SJ
Amino-terminal protein-protein interaction motif (POZ-domain) is responsible for activities of the promyelocytic leukemia zinc finger-retinoic acid receptor-alpha fusion protein.
Proc Natl Acad Sci USA
93
1996
3624
340
Tsai
S
Bartelmez
S
Sitnicka
E
Collins
S
Lymphohematopoietic progenitors immortalized by a retroviral vector harboring a dominant-negative retinoic acid receptor can recapitulate lymphoid, myeloid, and erythroid development.
Genes Dev
8
1994
2831
341
Corey
SJ
Locker
J
Oliveri
DR
Shekhter-Levin
S
Redner
RL
Penchansky
L
Gollin
SM
A non-classical translocation involving 17q12 (retinoic acid receptor alpha) in acute promyelocytic leukemia (APML) with atypical features.
Leukemia
8
1994
1350
342
Shaknovich R, Yeyati PL, Waxman S, Hellinger N, Nason-Burchenal K, Dmitrovsky E, Strutt P, Zelent AD, Licht JD: The promyelocytic leukemia zinc finger protein (PLZF) suppresses growth and induces apoptosis in the 32DCL3 myeloid cell line. Blood 88:555a, 1996 (abstr, suppl 1)
343
Mu
ZM
Chin
KV
Liu
JH
Lozano
G
Chang
KS
PML, a growth suppressor disrupted in acute promyelocytic leukemia.
Mol Cell Biol
14
1994
6858
344
Koken
MH
Linares-Cruz
G
Quignon
F
Viron
A
Chelbi-Alix
MK
Sobczak-Thepot
J
Juhlin
L
Degos
L
Calvo
F
de The
H
The PML growth-suppressor has an altered expression in human oncogenesis.
Oncogene
10
1995
1315
345
Le XF
Yang P
Chang
KS
Analysis of the growth and transformation suppressor domains of promyelocytic leukemia gene, PML.
J Biol Chem
271
1996
130
346
Hromas
R
Collins
SJ
Hickstein
D
Raskind
W
Deaven
LL
O'Hara
P
Hagen
FS
Kaushansky
K
A retinoic acid-responsive human zinc finger gene, MZF-1, preferentially expressed in myeloid cells.
J Biol Chem
266
1991
14183
347
Bavisotto
L
Kaushansky
K
Lin
N
Hromas
R
Antisense oligonucleotides from the stage-specific myeloid zinc finger gene MZF-1 inhibit granulopoiesis in vitro.
J Exp Med
174
1991
1097
348
Hoffman
SM
Hromas
R
Amemiya
C
Mohrenweiser
HW
The location of MZF-1 at the telomere of human chromosome 19q makes it vulnerable to degeneration in aging cells.
Leuk Res
20
1996
281
349
Vaziri
H
Dragowska
W
Allsopp
RC
Thomas
TE
Harley
CB
Lansdorp
PM
Evidence for a mitotic clock in human hematopoietic stem cells: Loss of telomeric DNA with age.
Proc Natl Acad Sci USA
91
1994
9857
350
Counter
CM
Gupta
J
Harley
CB
Leber
B
Bacchetti
S
Telomerase activity in normal leukocytes and in hematologic malignancies.
Blood
85
1995
2315
351
Morris
JF
Hromas
R
Rauscher
FJ
Characterization of the DNA-binding properties of the myeloid zinc finger protein MZF1: Two independent DNA-binding domains recognize two DNA consensus sequences with a common G-rich core.
Mol Cell Biol
14
1994
1786
352
Morris
JF
Rauscher
FJ
Davis
B
Klemsz
M
Xu
D
Tenen
D
Hromas
R
The myeloid zinc finger gene, MZF-1, regulates the CD34 promoter in vitro.
Blood
86
1995
3640
353
Perrotti
D
Melotti
P
Skorski
T
Casella
I
Peschle
C
Calabretta
B
Overexpression of the zinc finger protein MZF1 inhibits hematopoietic development from embryonic stem cells: Correlation with negative regulation of CD34 and c-myb promoter activity.
Mol Cell Biol
15
1995
6075
354
Hromas
R
Morris
J
Cornetta
K
Berebitsky
D
Davidson
A
Sha
M
Sledge
G
Rauscher
F
Aberrant expression of the myeloid zinc finger gene, MZF-1, is oncogenic.
Cancer Res
55
1995
3610
355
Hromas
R
Boswell
S
Shen
RN
Burgess
G
Davidson
A
Cornetta
K
Sutton
J
Robertson
K
Forced over-expression of the myeloid zinc finger gene MZF-1 inhibits apoptosis and promotes oncogenesis in interleukin-3-dependent FDCP.1 cells.
Leukemia
10
1996
1049
356
Robertson K, Hill D, Ewing C, Srour E, Grigsby S, Hromas R: The myeloid zinc finger gene MZF-1 inhibits retinoic acid-induced apoptosis and CD18 expression in HL60 cells. Blood 86:14a, 1995 (abstr, suppl 1)
357
Hui
P
Structural and functional characterization of human myeloid zinc finger gene-1 (MZF-1).
Diss Abstr Int
55
1994
2089
358
Sukhatme
VP
The Egr family of nuclear signal transducers.
Am J Kidney Dis
17
1991
615
359
Bedford
FK
Ashworth
A
Enver
T
Wiedemann
LM
HEX: A novel homeobox gene expressed during haematopoiesis and conserved between mouse and human.
Nucleic Acids Res
21
1993
1245
360
Lee
SL
Wang
Y
Milbrandt
J
Unimpaired macrophage differentiation and activation in mice lacking the zinc finger transactivation factor NGFI-A (EGR1).
Mol Cell Biol
16
1996
4566
361
Reddy
JC
Licht
JD
The WT1 Wilms' tumor suppressor gene: how much do we really know?
Biochim Biophys Acta
1287
1996
1
362
Rauscher
FJ
Morris
JF
Tournay
OE
Cook
DM
Curran
T
Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence.
Science
250
1990
1259
363
Haber
DA
Park
S
Maheswaran
S
Englert
C
Re
GG
Hazen-Martin
DJ
Sens
DA
Garvin
AJ
WT1-mediated growth suppression of Wilms' tumor cells expressing a WT1 splicing variant.
Science
262
1993
2057
364
Luo
XN
Reddy
JC
Yeyati
PL
Idris
AH
Hosono
S
Haber
DA
Licht
JD
Atweh
GF
The tumor suppressor gene WT1 inhibits ras-mediated transformation.
Oncogene
11
1995
743
365
Werner
H
Shen-Orr
Z
Rauscher
FJ
Morris
JF
Roberts
CT Jr
Leroith
D
Inhibition of cellular proliferation by the Wilms' tumor suppressor WT1 is associated with suppression of insulin-like growth factor I receptor gene expression.
Mol Cell Biol
15
1995
3516
366
Englert
C
Hou
X
Maheswaran
S
Bennett
P
Ngwu
C
Re
GG
Garvin
AJ
Rosner
MR
Haber
DA
WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis.
EMBO J
14
1995
4662
367
Inoue
K
Sugiyama
H
Ogawa
H
Nakagawa
M
Yamagami
T
Miwa
H
Kita
K
Hiraoka
A
Masaoka
T
Nasu
K
Kyo
T
Dohy
H
Nakauchi
H
Ishidate
T
Akiyama
T
Kishimoto
T
WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia.
Blood
84
1994
3071
368
Fraizer
GC
Patmasiriwat
P
Zhang
X
Saunders
GF
Expression of the tumor suppressor gene WT1 in both human and mouse bone marrow.
Blood
86
1995
4704
369
Phelan
SA
Lindberg
C
Call
KM
Wilms' tumor gene, WT1, mRNA is down-regulated during induction of erythroid and megakaryocytic differentiation of K562 cells.
Cell Growth Differ
5
1994
677
370
Sekiya
M
Adachi
M
Hinoda
Y
Imai
K
Yachi
A
Downregulation of Wilms' tumor gene (wt1) during myelomonocytic differentiation in HL60 cells.
Blood
83
1994
1876
371
Kreidberg
JA
Sariola
H
Loring
JM
Maeda
M
Pelletier
J
Housman
D
Jaenisch
R
WT-1 is required for early kidney development.
Cell
74
1993
679
372
Miwa
H
Beran
M
Saunders
GF
Expression of the Wilms' tumor gene (WT1) in human leukemias.
Leukemia
6
1992
405
373
Hoffman
B
Liebermann
DA
Selvakumaran
M
Nguyen
HQ
Role of c-myc in myeloid differentiation, growth arrest and apoptosis.
Curr Top Microbiol Immunol
211
1996
17
374
Brieger
J
Weidmann
E
Fenchel
K
Mitrou
PS
Hoelzer
D
Bergmann
L
The expression of the Wilms' tumor gene in acute myelocytic leukemias as a possible marker for leukemic blast cells.
Leukemia
8
1994
2138
375
Algar
EM
Khromykh
T
Smith
SI
Blackburn
DM
Bryson
GJ
Smith
PJ
A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in myeloid leukaemia cell lines.
Oncogene
12
1996
1005
376
Yamagami
T
Sugiyama
H
Inoue
K
Ogawa
H
Tatekawa
T
Hirata
M
Kudoh
T
Akiyama
T
Murakami
A
Maekawa
T
Growth inhibition of human leukemic cells by WT1 (Wilms' tumor gene) antisense oligodeoxynucleotides: Implications for the involvement of WT1 in leukemogenesis.
Blood
87
1996
2878
377
Pritchard-Jones
K
Renshaw
J
King-Underwood
L
The Wilms tumour (WT1) gene is mutated in a secondary leukaemia in a WAGR patient.
Hum Mol Genet
3
1994
1633
378
Reddy
JC
Morris
JC
Wang
J
English
MA
Haber
DA
Shi
Y
Licht
JD
WT1-mediated transcriptional activation is inhibited by dominant negative mutant proteins.
J Biol Chem
270
1995
10878
379
Englert
C
Vidal
M
Maheswaran
S
Ge
Y
Ezzell
RM
Isselbacher
KJ
Haber
DA
Truncated WT1 mutants alter the subnuclear localization of the wild-type protein.
Proc Natl Acad Sci USA
92
1995
11960
380
Moffett
P
Bruening
W
Nakagama
H
Bardeesy
N
Housman
D
Housman
DE
Pelletier
J
Antagonism of WT1 activity by protein self-association.
Proc Natl Acad Sci USA
92
1995
11105
381
McCann
S
Sullivan
J
Guerra
J
Arcinas
M
Boxer
LM
Repression of the c-myb gene by WT1 protein in T and B cell lines.
J Biol Chem
270
1995
23785
382
Hoffman-Liebermann
B
Liebermann
DA
Suppression of c-myc and c-myb is tightly linked to terminal differentiation induced by IL6 or LIF and not growth inhibition in myeloid leukemia cells.
Oncogene
6
1991
903
383
Anfossi
G
Gewirtz
AM
Calabretta
B
An oligomer complementary to c-myb-encoded mRNA inhibits proliferation of human myeloid leukemia cell lines.
Proc Natl Acad Sci USA
86
1989
3379
384
McGinnis
W
Garber
RL
Wirz
J
Kuroiwa
A
Gehring
WJ
A homologous protein-coding sequence in Drosophila homeotic genes and its conservation in other metazoans.
Cell
37
1984
403
385
Scott
MP
Weiner
AJ
Structural relationships among genes that control development: Sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila.
Proc Natl Acad Sci USA
81
1984
4115
386
Krumlauf
R
Hox genes in vertebrate development.
Cell
78
1994
191
387
Zhang P, Benson GV, Rhoades KL, Maas RL, Tenen DG: HoxA-10 deficient mice exhibit increased myelopoiesis and overproliferation of myeloid colony forming units. Proc Natl Acad Sci USA (submitted)
388
Thorsteinsdottir
U
Sauvageau
G
Hough
MR
Dragowska
W
Lansdorp
PM
Lawrence
HJ
Largman
C
Humphries
RK
Overexpression of HoxA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia.
Mol Cell Biol
17
1996
495
389
Satokata
I
Benson
GV
Maas
RL
Sexually dimorphic sterility phenotypes in Hoxa10-deficient mice.
Nature
374
1995
460
390
Lawrence
HJ
Helgason
CD
Sauvageau
G
Fong
S
Izon
D
Humphries
RK
Largman
C
Mice bearing targeted interruptions of the homeobox gene hoxa9 have defects in myeloid, erythroid, and lymphoid hematopoiesis.
Blood
89
1997
1922
391
Perkins
AC
Cory
S
Conditional immortalization of mouse myelomonocytic, megakaryocytic and mast cell progenitors by the Hox-2.4 homeobox gene.
EMBO J
12
1993
3835
392
Perkins
A
Kongsuwan
K
Visvader
J
Adams
JM
Cory
S
Homeobox gene expression plus autocrine growth factor production elicits myeloid leukemia.
Proc Natl Acad Sci USA
87
1990
8398
393
Deguchi
Y
Kirschenbaum
A
Kehrl
JH
A diverged homeobox gene is involved in the proliferation and lineage commitment of human hematopoietic progenitors and highly expressed in acute myelogenous leukemia.
Blood
79
1992
2841
394
Allen
JD
Adams
JM
Enforced expression of Hlx homeobox gene prompts myeloid cell maturation and altered adherence properties of T cells.
Blood
81
1993
3242
395
Lill
MC
Fuller
JF
Herzig
R
Crooks
GM
Gasson
JC
The role of the homeobox gene, HOX B7, in human myelomonocytic differentiation.
Blood
85
1995
692
396
Hromas
R
Radich
J
Collins
S
PCR Cloning of an orphan homeobox gene (PRH) preferentially expressed in myeloid and liver cells.
Biochem Biophys Res Commun
195
1993
976
397
Crompton
MR
Bartlett
TJ
Macgregor
AD
Manfioletti
G
Buratti
E
Giancotti
V
Goodwin
GH
Identification of a novel vertebrate homeobox gene expressed in haematopoietic cells.
Nucleic Acids Res
20
1992
5661
398
Manfioletti
G
Gattei
V
Buratti
E
Rustighi
A
De Iuliis
A
Aldinucci
D
Goodwin
GH
Pinto
A
Differential expression of a novel proline-rich homeobox gene (Prh) in human hematolymphopoietic cells.
Blood
85
1995
1237
399
Yu
BD
Hess
JL
Horning
SE
Brown
GAJ
Korsmeyer
SJ
Altered Hox expression and segmental identity in Mll-mutant mice.
Nature
378
1995
505
400
Domer
PH
Fakharzadeh
SS
Chen
CS
Jockel
J
Johansen
L
Silverman
GA
Kersey
JH
Korsmeyer
SJ
Acute mixed-lineage leukemia t(4; 11)(q21; q23) generates a MLL-AF4 fusion product.
Proc Natl Acad Sci USA
90
1993
7884
401
Corral
J
Forster
A
Thompson
S
Lampert
F
Kaneko
Y
Slater
R
Kroes
WG
Vanderschoot
CE
Ludwig
WD
Karpas
A
Pocock
C
Cotter
F
Rabbitts
TH
Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation.
Proc Natl Acad Sci USA
90
1993
8538
402
Chang
CP
Shen
WF
Rozenfeld
S
Lawrence
HJ
Largman
C
Cleary
ML
Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins.
Genes Dev
9
1995
663
403
Kamps
MP
Baltimore
D
E2A-Pbx1, the t(1; 19) translocation protein of human pre-B-cell acute lymphocytic leukemia, causes acute myeloid leukemia in mice.
Mol Cell Biol
13
1993
351
404
Luscher
B
Eisenman
RN
New light on Myc and Myb. Part II. Myb.
Genes Dev
4
1990
2235
405
Golay
J
Basilico
L
Loffarelli
L
Songia
S
Broccoli
V
Introna
M
Regulation of hematopoietic cell proliferation and differentiation by the myb oncogene family of transcription factors.
Int J Clin Lab Res
26
1996
24
406
Biedenkapp
H
Borgmeyer
U
Sippel
AE
Klempnauer
KH
Viral myb oncogene encodes a sequence-specific DNA-binding activity.
Nature
335
1988
835
407
Melotti
P
Ku
D-H
Calabretta
B
Regulation of the expression of the hematopoietic stem cell antigen CD34: Role of c-myb.
J Exp Med
179
1994
1023
408
Burn
TC
Satterthwaite
AB
Tenen
DG
The human CD34 hematopoietic stem cell antigen promoter and a 3′ enhancer direct hematopoietic expression in tissue culture.
Blood
80
1992
3051
409
Krause
DS
Fackler
MJ
Civin
CI
May
WS
CD34: Structure, biology, and clinical utility.
Blood
87
1996
1
410
Shapiro
LH
Myb and Ets proteins cooperate to transactivate an early myeloid gene.
J Biol Chem
270
1995
8763
411
Burk
O
Mink
S
Ringwald
M
Klempnauer
KH
Synergistic activation of the chicken mim-1 gene by v-myb and C/EBP transcription factors.
EMBO J
12
1993
2027
412
Oelgeschlager
M
Janknecht
R
Krieg
J
Schreek
S
Luscher
B
Interaction of the co-activator CBP with Myb proteins: Effects on Myb-specific transactivation and on the cooperativity with NF-M.
EMBO J
15
1996
2771
413
Cogswell
JP
Cogswell
PC
Kuehl
WM
Cuddihy
AM
Bender
TM
Engelke
U
Marcu
KB
Ting
JPY
Mechanism of c-myc regulation by c-Myb in different cell lineages.
Mol Cell Biol
13
1993
2858
414
Henriksson
M
Luscher
B
Proteins of the Myc network: Essential regulators of cell growth and differentiation.
Adv Cancer Res
68
1996
109
415
Luscher
B
Eisenman
RN
New light on Myc and Myb. Part I. Myc.
Genes Dev
4
1990
2025
416
Selvakumaran
M
Liebermann
D
Hoffman-Liebermann
B
Myeloblastic leukemia cells conditionally blocked by myc-estrogen receptor chimeric transgenes for terminal differentiation coupled to growth arrest and apoptosis.
Blood
81
1993
2257
417
Ayer
DE
Eisenman
RN
A switch from Myc:Max to Mad:Max heterocomplexes accompanies monocyte/macrophage differentiation.
Genes Dev
7
1993
2110
418
Larsson
LG
Pettersson
M
Oberg
F
Nilsson
K
Luscher
B
Expression of mad, mxi1, max and c-myc During Induced Differentiation of Hematopoietic Cells — Opposite regulation of mad and c-myc.
Oncogene
9
1994
1247
419
Perkins
ND
Edwards
NL
Duckett
CS
Agranoff
AB
Schmid
RM
Nabel
GJ
A cooperative interaction between NF-kappa-B and Sp1 is required for HIV-1 enhancer activation.
EMBO J
12
1993
3551
420
Grove
M
Plumb
M
C/EBP, NF-kappa-B, and c-Ets family members and transcriptional regulation of the cell-specific and inducible macrophage inflammatory protein-1-alpha immediate-early gene.
Mol Cell Biol
13
1993
5276
421
Stein
B
Baldwin
AS Jr
Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity between C/EBP and NF-kB.
Mol Cell Biol
13
1993
7191
422
Weih
F
Carrasco
D
Durham
SK
Barton
DS
Rizzo
CA
Ryseck
RP
Lira
SA
Bravo
R
Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family.
Cell
80
1995
331
423
Tkachuk
DC
Kohler
S
Cleary
ML
Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias.
Cell
71
1992
691
424
Thirman
MJ
Gill
HJ
Burnett
RC
Mbangkollo
D
McCabe
NR
Kobayashi
H
Ziemin-van der Poel S
Kaneko
Y
Morgan
R
Sandberg
AA
Chaganti
RSK
Larson
RA
LeBeau
MM
Diaz
MO
Rowley
JD
Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations.
N Engl J Med
329
1993
909
425
Zeleznik-Le
NJ
Harden
AM
Rowley
JD
11q23 translocations split the “AT-hook” cruciform DNA-binding region and the transcriptional repression domain from the activation domain of the mixed-lineage leukemia (MLL) gene.
Proc Natl Acad Sci USA
91
1994
10610
426
Fidanza
V
Melotti
P
Yano
T
Nakamura
T
Bradley
A
Canaani
E
Calabretta
B
Croce
CM
Double knockout of the ALL-1 gene blocks hematopoietic differentiation in vitro.
Cancer Res
56
1996
1179
427
Mashal
R
Shtalrid
M
Talpaz
M
Kantarjian
H
Smith
L
Beran
M
Cork
A
Trujillo
J
Gutterman
J
Deisseroth
A
Rearrangement and expression of p53 in the chronic phase and blast crisis of chronic myelogenous leukemia.
Blood
75
1990
180
428
Nakai
H
Misawa
S
Toguchida
J
Yandell
DW
Ishizaki
K
Frequent p53 gene mutations in blast crisis of chronic myelogenous leukemia, especially in myeloid crisis harboring loss of a chromosome 17p.
Cancer Res
52
1992
6588
429
Lanza
F
Bi
S
Role of p53 in leukemogenesis of chronic myeloid leukemia.
Stem Cells
13
1995
445
430
Zauberman
A
Lupo
A
Oren
M
Identification of p53 target genes through immune selection of genomic DNA: The cyclin G gene contains two distinct p53 binding sites.
Oncogene
10
1995
2361
431
Soddu
S
Blandino
G
Citro
G
Scardigli
R
Piaggio
G
Ferber
A
Calabretta
B
Sacchi
A
Wild-type p53 gene expression induces granulocytic differentiation of HL-60 cells.
Blood
83
1994
2230
432
Bohmann
D
Bos
TJ
Admon
A
Nishimura
T
Vogt
PK
Tjian
R
Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1.
Science
238
1987
1386
433
Mollinedo
F
Gajate
C
Tugores
A
Flores
I
Naranjo
JR
Differences in expression of transcription factor AP-1 in human promyelocytic HL-60 cells during differentiation towards macrophages versus granulocytes.
Biochem J
294
1993
137
434
Lord
KA
Abdollahi
A
Hoffman-Liebermann
B
Liebermann
DA
Proto-oncogenes of the fos/jun family of transcription factors are positive regulators of myeloid differentiation.
Mol Cell Biol
13
1993
841
435
Salbert
G
Fanjul
A
Piedrafita
FJ
Lu
XP
Kim
SJ
Tran
P
Pfahl
M
Retinoic acid receptors and retinoid-X receptor-alpha down-regulate the transforming growth factor-beta(1) promoter by antagonizing AP-1 activity.
Mol Endocrinol
7
1993
1347
436
Doucas
V
Brockes
JP
Yaniv
M
Dethe
H
Dejean
A
The PML-retinoic acid receptor-alpha translocation converts the receptor from an inhibitor to a retinoic acid-dependent activator of transcription factor-AP-1.
Proc Natl Acad Sci USA
90
1993
9345
437
Satake
M
Nomura
S
Yamaguchpiiwai
Y
Takahama
Y
Hashimot
Y
Niki
M
Kitamura
Y
Ito
Y
Expression of the runt domain-encoding PEBP2 alpha genes in T cells during thymic development.
Mol Cell Biol
15
1995
1662
438
Sposi
NM
Zon
LI
Care
A
Valtieri
M
Testa
U
Gabbianelli
M
Mariani
G
Bottero
L
Mather
C
Orkin
SH
Peschle
C
Cell cycle-dependent initiation and lineage-dependent abrogation of GATA-1 expression in pure differentiating hematopoietic progenitors.
Proc Natl Acad Sci USA
89
1992
6353
439
Tsai
SF
Strauss
E
Orkin
SH
Functional analysis and in vivo footprinting implicate the erythroid transcription factor GATA-1 as a positive regulator of its own promoter.
Genes Dev
5
1991
919
440
Zon
LI
Youssoufian
H
Mather
C
Lodish
HF
Orkin
SH
Activation of the erythropoietin receptor promoter by transcription factor GATA-1.
Proc Natl Acad Sci USA
88
1991
10638
441
Visvader
J
Adams
JM
Megakaryocytic differentiation in 416B myeloid cells by GATA-2 and GATA-3 transgenes or 5-azacytidine is tightly coupled to GATA-1 expression.
Blood
82
1993
1493
442
Ihle
JN
Cytokine receptor signalling.
Nature
377
1995
591
443
Carlesso
N
Frank
DA
Griffin
JD
Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl.
J Exp Med
183
1996
811
444
Tsui
HW
Siminovitch
KA
Desouza
L
Tsui
FWL
Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene.
Nat Genet
4
1993
124
445
Shultz
LD
Schweitzer
PA
Rajan
TV
Yi
TL
Ihle
JN
Matthews
RJ
Thomas
ML
Beier
DR
Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene.
Cell
73
1993
1445
446
Bollag
G
Clapp
DW
Shih
S
Adler
F
Zhang
YY
Thompson
P
Lange
BJ
Freedman
MH
Mccormick
F
Jacks
T
Shannon
K
Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells.
Nat Genet
12
1996
144
447
Largaespada
DA
Brannan
CI
Jenkins
NA
Copeland
NG
Nf1 deficiency causes Ras-mediated granulocyte macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia.
Nat Genet
12
1996
137
448
Perez
C
Coeffier
E
Moreau-Gachelin
F
Wietzerbin
J
Benech
PD
Involvement of the transcription factor PU.1/Spi-1 in myeloid cell-restricted expression of an interferon-inducible gene encoding the human high-affinity Fc gamma receptor.
Mol Cell Biol
14
1994
5023
449
Feinman
R
Qiu
WQ
Pearse
RN
Nikolajczyk
BS
Sen
R
Sheffery
M
Ravetch
JV
PU.1 and an HLH family member contribute to the myeloid-specific transcription of the Fc-gammaRIIIA promoter.
EMBO J
13
1994
3852
450
Rosmarin
AG
Caprio
D
Levy
R
Simkevich
C
CD18 (β2 leukocyte integrin) promoter requires PU.1 transcription factor for myeloid activity.
Proc Natl Acad Sci USA
92
1995
801
451
Srikanth
S
Rado
TA
A 30-base pair element is responsible for the myeloid-specific activity of the human neutrophil elastase promoter.
J Biol Chem
269
1994
32626
452
Carvalho
M
Derse
D
The PU.1/Spi-1 proto-oncogene is a transcriptional regulator of a lentivirus promoter.
J Virol
67
1993
3885
453
Maury
W
Monocyte maturation controls expression of equine infectious anemia virus.
J Virol
68
1994
6270
454
Himmelmann
A
Thevenin
C
Harrison
K
Kehrl
JH
Analysis of the Bruton's tyrosine kinase gene promoter reveals critical PU1 and SP1 sites.
Blood
87
1996
1036
455
Mitelman F, Heim S: Cancer Cytogentics. New York, NY, Wiley-Liss, 1995, p 69
Sign in via your Institution