ADAPTIVE IMMUNITY in mammals depends on the generation of a vast repertoire of Ig and T-cell receptor (TCR) specificities expressed on individual B and T lymphocytes. Antigen receptor diversity is created by the assembly of variable region gene segments by a process of somatic DNA rearrangement known as V(D)J recombination. Additional genetic alterations in Ig genes occur during immune responses through isotype class switch recombination and somatic hypermutation of variable regions in germinal center B cells. Thus, lymphocytes breach genomic integrity at several developmental stages to expand the germline genetic program. A central feature of neoplasms in the lymphoid lineage is chromosomal translocations, which occur in the majority of non-Hodgkin's lymphomas (NHL) as well as in many acute leukemias and plasma cell neoplasms. Translocations in NHL characteristically juxtapose a cellular proto-oncogene with one of the antigen receptor loci, leading to deregulated oncogene expression. It has been hypothesized that such oncogenic translocations arise as byproducts of physiologic gene rearrangement processes, although evidence to date has been mostly circumstantial. In recent years, there have been important advances in several areas that make it appropriate to re-examine the connection between genetic instability at the antigen receptor loci and the pathogenesis of lymphoid malignancies. An understanding of the major steps of V(D)J recombination at both the genetic and biochemical levels has emerged, suggesting ways in which the recombinase mechanism may protect broken DNA ends from exposure to inappropriate repair mechanisms. It is now apparent that genetic plasticity in lymphocytes, especially involving the Ig loci in B cells, is much greater than previously appreciated. In particular, B-lineage cells are now known to undergo V(D)J recombination and revise Ig locus variable regions in response to antigenic stimulation. Germinal center B cells also undergo somatic hypermutation of Ig genes, a process that is now understood to involve DNA strand breaks, as well as Ig isotype switch recombination. Inasmuch as the most common types of nodal B-cell NHL are postulated to arise in the germinal center, these recent insights suggest that genomic instability that occurs in the context of immune responses may contribute to the genetic alterations leading to lymphoid neoplasia.

Given the vigor with which chromosomal DNA is broken and repaired in lymphocytes during lineage development and antigen responses, it is perhaps appropriate to ask what elements of antigen receptor diversification processes limit generalized genomic instability, ie, what safety features prevent the occurrence of oncogenic events in most individuals. Clues to such tumor-suppressor mechanisms may emerge from the study of genes responsible for hereditary lymphoma susceptibility disorders, including ataxia-telangiectasia (A-T), Nijmegen breakage syndrome (NBS), and Bloom's syndrome. In the absence of genetic predisposition, toxic exposures or immune system alterations (eg, such as occurs in acquired immunodeficiency syndrome [AIDS]) may interfere with mechanisms that assure genetic safety in the resolution of DNA breaks. Further understanding of antigen receptor gene diversification in lymphocytes and the regulation of these processes in immunity may therefore yield testable hypotheses about the causes of lymphoma.

Mechanism of V(D)J recombination.

Antigen receptor diversity is generated during development of B and T cells by a process of somatic gene rearrangement, wherein variable regions are assembled by apposition of germline variable (V), diversity (D), and joining (J) segments (or V and J segments) to form a contiguous exon (reviewed in Alt et al1). Sequence diversity is, in part, combinatorial, achieved by selection among multiple versions of each type of segment. V(D)J recombination may involve segments located more than 2 Mb apart, yet almost always occurs in cis. During B- and T-cell development, rearrangement of antigen receptor genes occurs in a stepwise fashion to generate proteins that interact with a membrane signaling complex. Successive versions of this complex drive cellular expansion, mediate cellular differentiation, and deliver survival and/or death signals that shape the composition of the immune system (reviewed in Willerford et al2). Thus, V(D)J rearrangement is not only a product of lymphoid differentiation, but is also a critical mediator of the development process. Many of the genes involved in V(D)J recombination have been identified, and some of the steps are beginning to be understood at a biochemical level. The physiology of this process has also been studied in mutant mice generated by gene targeting strategies. A summary is provided in Table 1.

Table 1.

Genes Involved in V(D)J Recombination

Gene Properties Role in V(D)J Recombination Other Roles
Rag-1  Endonuclease  Initiation  None known  
Rag-2 Endonuclease  Initiation  None known  
DNA-PKcs Protein kinase  Rejoining coding ends  Switch recombination; DNA repair  
Ku70  DNA end-binding; stimulates DNA ligase Rejoining coding and signal ends  Switch recombination; DNA repair; growth  
Ku86  DNA end-binding; stimulates DNA ligase; TdT recruitment  Rejoining coding and signal ends  Switch recombination; DNA repair; growth  
XRCC4  Recruits DNA ligase  Rejoining coding and signal ends  DNA repair; brain development  
DNA Ligase IV  End joining  Rejoining coding and signal ends  DNA repair; brain development  
TdT Template-independent base addition  Diversifies coding joints None known 
Gene Properties Role in V(D)J Recombination Other Roles
Rag-1  Endonuclease  Initiation  None known  
Rag-2 Endonuclease  Initiation  None known  
DNA-PKcs Protein kinase  Rejoining coding ends  Switch recombination; DNA repair  
Ku70  DNA end-binding; stimulates DNA ligase Rejoining coding and signal ends  Switch recombination; DNA repair; growth  
Ku86  DNA end-binding; stimulates DNA ligase; TdT recruitment  Rejoining coding and signal ends  Switch recombination; DNA repair; growth  
XRCC4  Recruits DNA ligase  Rejoining coding and signal ends  DNA repair; brain development  
DNA Ligase IV  End joining  Rejoining coding and signal ends  DNA repair; brain development  
TdT Template-independent base addition  Diversifies coding joints None known 

V(D)J recombination is site-specific and is targeted by characteristic recognition signal sequences (RSS) that flank the borders of recombining variable region gene segments (Fig 1). RSS are composed of conserved heptamer and AT-rich nonamer sequences, separated by either a 12 or 23 nucleotide spacer. V(D)J recombination is initiated by DNA breaks catalyzed by the lymphoid-specific recombinase components Rag-1 and Rag-2, which occur precisely at the border between RSS and coding segment.3-5 This cleavage reaction occurs efficiently in vitro, beginning with nicking of 1 strand and followed by transesterification of the opposing phosphodiester bond to produce a blunt cut at the signal end and a sealed hairpin structure at the coding end. V(D)J rearrangement occurs between RSS with dissimilar spacer lengths (known as the 12/23 rule), a property that prevents nonproductive V to V or J to J rearrangements.1 This reflects an important, intrinsic property of Rag-mediated DNA scission: creation of 2 DNA breaks is coupled6,7 and occurs within a single synaptic complex that remains assembled after cleavage, where it facilitates efficient rejoining.8 Mutational inactivation of either Rag-1 or Rag-2 in mice prevents V(D)J recombination and blocks T- and B-cell development at an early progenitor stage.9,10 Mutations in the Rag genes account for a subset of autosomally inherited severe combined immunodeficiency in humans.11 Point mutations of Rag-1 or Rag-2 reducing the efficiency of V(D)J recombination have also been found in Omenn syndrome, an immunodeficiency characterized by activated, oligoclonal T cells and hypereosinophilia.12 

Fig. 1.

Mechanisms for antigen receptor gene diversification in lymphocytes. (A) V(D)J recombination is initiated by DNA cleavage at RSS (triangles) bordering variable region gene segments. Rejoining of ends is reciprocal and requires the DNA-PKcs and Ku proteins, as well as XRCC4 and DNA ligase IV. (B) Class switch recombination is targeted by an unknown mechanism involving switch regions located upstream of constant region coding exons. Like V(D)J recombination, rejoining is reciprocal and requires the DNA-PKcs and Ku proteins. (C) Somatic hypermutation is targeted to Ig variable regions by a transcriptional mechanism. DNA breaks occur in the course of the mutation process, which leads to base substitutions as well as small insertions and deletions.

Fig. 1.

Mechanisms for antigen receptor gene diversification in lymphocytes. (A) V(D)J recombination is initiated by DNA cleavage at RSS (triangles) bordering variable region gene segments. Rejoining of ends is reciprocal and requires the DNA-PKcs and Ku proteins, as well as XRCC4 and DNA ligase IV. (B) Class switch recombination is targeted by an unknown mechanism involving switch regions located upstream of constant region coding exons. Like V(D)J recombination, rejoining is reciprocal and requires the DNA-PKcs and Ku proteins. (C) Somatic hypermutation is targeted to Ig variable regions by a transcriptional mechanism. DNA breaks occur in the course of the mutation process, which leads to base substitutions as well as small insertions and deletions.

Close modal

An important observation regarding the rejoining of DNA ends created by Rag-mediated DNA scission is that all somatic cells possess the required machinery, which overlaps with general cellular pathways responsible for repairing double-strand DNA breaks.3,13,14There is reciprocal rejoining of both coding and signal ends, so that, depending on the respective orientation of recombining segments, the intervening DNA is either excised as a circle15 or inverted with re-establishment of chromosomal continuity. The distinct structures of signal and coding ends created by Rag-mediated DNA cleavage are processed by different pathways.16 Signal ends are usually religated without gain or loss of germline sequence. In contrast, coding end processing is inherently inaccurate: first, opening of the sealed hairpin structure may occur asymmetrically, generating short complementary sequences at coding joints recognized as P elements; second, open coding ends frequently lose several base pairs to nuclease activity during processing; finally, expression of terminal deoxynuclotidyl transferase (TdT) in developing lymphocytes adds bases (N-nucleotides) in a template-independent fashion. These properties produce extreme sequence diversity at the site of V(D)J joins, which correspond to the antigen contact residues of TCR and Ig molecules and act to expand the diversity of the immune repertoire.

A central component of the rejoining reaction is the DNA-dependent protein kinase (DNA-PK) complex, which includes the DNA-PK catalytic subunit (DNA-PKcs), along with the Ku70 and Ku86 nuclear antigens.17 DNA-PKcs is a member of the PI-3 kinase gene family, which includes the ATM gene, responsible for the lymphoma susceptibility and neuro-degenerative disorder A-T. DNA-PKcs is mutated in the mouse Scid strain,18-20 which, along with mice carrying insertional or targeted DNA-PKcs mutations, exhibits defective V(D)J rearrangement and impaired lymphocyte development.21-23 Defects in DNA-PKcs selectively impair coding joint formation, whereas signal joints are relatively normal.24,25 The infrequent coding joints recovered from DNA-PKcs–deficient cells often exhibit large deletions, which suggests that alternative pathways for rejoining engender a lesser degree of protection for DNA ends created during V(D)J recombination. The Ku70 and Ku86 nuclear proteins exhibit DNA end-binding activity and, in concert with DNA, activate the kinase function of the DNA-PKcs.17 V(D)J recombination is impaired in cell lines deficient in either Ku70 or Ku86.13,26,27 However, in contrast to the defect with DNA-PKcs mutations, Ku70 and Ku86 are required for rejoining both coding and signal ends, indicating that these proteins have functional activities independent of the DNA-PK complex. Mice lacking Ku86 or Ku 70 have severe defects in T- and B-cell development, although leaky development of T cells is observed in Ku70−/− mice.28-31 In addition, both types of mice exhibit growth retardation, indicating that the Ku proteins function independently of the DNA-PKcs in general growth regulation.

The final step in the V(D)J reaction involves ligation of DNA ends. Two essential components are the XRCC4 gene, which complements the defect in V(D)J recombination and DNA repair in the radiation-sensitive XR-1 cell line,32 and DNA ligase IV.33 XRCC4 appears to facilitate recruitment of the ligase to the rejoining complex.34,35 Targeted null mutation of either XRCC4 or DNA ligase IV produces a similar phenotype, with an arrest in lymphoid development at an early progenitor stage. Interestingly, both of these mutations lead to severe defects in brain development stemming from death of postmitotic neurons, raising the possibility that some form of DNA rearrangement is required to form the nervous system.36,37 Along these lines, it has recently been determined that neural cadherin-like genes are organized into variable and constant region clusters reminiscent of Ig and TCR loci.38 

The V(D)J recombination mechanism is shared by all 7 TCR and Ig loci. However, the process is tightly controlled, so that rearrangement of individual loci is restricted to the appropriate cell lineage and developmental stage.2,39 Rag-mediated DNA cleavage requires that target locus chromatin be in an open or accessible conformation.3,40 Changes in chromatin structure accompany transcription of antigen receptor loci in their germline configuration, which invariably occurs before rearrangement and appears to play a key role in regulating the initiation of the V(D)J reaction. This conclusion is based on an elegant series of studies using gene transfection, transgenic recombination substrates, and knockouts of cis-regulatory elements that demonstrate that rearrangement requires the enhancer and promoter elements that regulate germline transcription.39,41 42 It is not known whether germline transcription acts only in a permissive way to facilitate recombinase access or plays a more direct role in targeting V(D)J recombination to the appropriate locus.

Ig class switch recombination.

After immune stimulation, antigen-reactive B cells frequently undergo isotype class switching, wherein exon clusters encoding the constant regions for Igγ, Igα, or Igε isotypes are juxtaposed with a functional V(D)J-rearranged variable region to produce antibody molecules with the same antigen specificity but with specialized effector functions determined by the incoming constant region (reviewed in Stavnezer43). These functions may include prolonged plasma half-life, differential binding to distinct Fc receptor types on effector cells, and exogenous secretion by mucosal epithelium. The constant region clusters for the different IgH isotypes are located 3′ of Cμ and Cδ within the IgH locus. Class switching involves a nonhomologous recombination event, resulting in the looping out of intervening sequences.44 Recombination is targeted by characteristic switch regions that span 2 to 10 kb and are located 5′ of Cμ and each of the constant region clusters, excepting Cδ (Fig 1). Switch regions contain characteristic tandem arrays of short repetitive sequences; however, there appears to be no sequence specificity in switch region breakpoints.45,46 It is not known how switch recombination is initiated, but the characteristic targets are distinct from the RSS used in V(D)J recombination. Correspondingly, class switching proceeds efficiently in the absence of Rag-1 or Rag-2, whether driven by CD40 in cultured Rag-deficient pro-B cells or in mature B cells from Rag-null mice carrying a rearranged IgH allele.47 48 

Class switching is regulated to a large extent by interaction with T cells and includes signals from a variety of cytokines as well as by CD40 ligand/CD40 interactions. These effects are mediated in part via regulation of germline transcription, which originates at noncoding I exons located 5′ of the constant region clusters.43,49 Germline transcription is controlled by upstream promoter regions as well as enhancer/LCR elements within the IgH locus.50-52 The mechanistic role of transcription in switch recombination has been investigated using gene targeting techniques in mice.49,50 53-57 These studies suggest that transcription alone is insufficient for activation of class switching, unless the appropriate signals for transcript processing by RNA splicing are included. Thus, germline transcription appears to play more than a minimal function in regulating locus accessibility, and either the RNA splicing machinery or the processed transcript itself could play a role in the switch recombination process.

Switch recombination resembles V(D)J recombination in that DNA ends are rejoined in a reciprocal fashion.44 This suggests that the creation of 2 DNA breaks may be coupled, occurring within a synaptic complex that sequesters DNA ends and facilitates rejoining. In support of this notion, rejoining of DNA breaks created during class switch recombination requires the DNA-PK complex. Switch recombination is impaired in pro-B cells from Scid mice,47 as well as in mice carrying rearranged Ig genes that lack Ku70 or Ku86.58 59 Thus, V(D)J and class switch recombination represent 2 distinct ways in which physiologic DNA breaks are created in the IgH locus in B cells, whereas resolution of these breaks shares a common pathway.

Somatic hypermutation.

The Ig repertoire created by V(D)J recombination during B-cell development is further diversified during immune responses by the induction of somatic hypermutation in the V regions of IgH and IgL genes (reviewed in Neuberger and Milstein60 and Storb61). In germinal center B cells, mutations are introduced into V region gene segments at a rate of approximately 1/1,000 bp per generation (Fig 1). Subsequent selection processes favor survival and expansion of cells with increased affinity for antigen. Somatic hypermutation of Ig genes is confined to a region within about 1.5 kb downstream of the promoter, and extensive studies using transgenic mice indicate that transcription and somatic hypermutation are intimately linked.62 Models for the mechanism of somatic hypermutation have focused on DNA repair processes, and these have been tested by examination of humans and mice with mutations involving several of these pathways. A role for nucleotide excision repair has been largely excluded by the finding that somatic hypermutation is intact in humans with mutations in several genes responsible for Xeroderma Pigmentosum or Cockayne syndrome, as well as in mice with targeted mutation of XPC, XPA, or XPD.63Studies in mice with mutations in DNA mismatch repair components PMS2 and MSH2 have yielded some conflicting results regarding a potential role in somatic hypermutation (discussed in Wood64 and Kelsoe65). Moreover, the recent finding that MSH2 is required for effective humoral immune responses and maturation of germinal centers66 complicates the interpretation of these studies. Somatic hypermutation most commonly involves base substitutions; however, recent studies have indicated that insertions or deletions may also occur with significant frequency.67,68 These imply that somatic hypermutation involves DNA strand breaks, a hypothesis supported by recent experiments in a constitutively hypermutating Burkitt's lymphoma cell line.69 By artificially expressing TdT, these investigators found that a substantial fraction of acquired mutations in IgH V regions exhibited nontemplated base additions, indicating that the mutation mechanism involved free DNA ends. These findings raise important questions, including whether DNA breaks are an essential element of the somatic hypermutation mechanism, whether such breaks involve both DNA strands, and, if so, whether rejoining involves any of the elements shared between V(D)J and class switch recombination.

Genetic plasticity of Ig genes in B cells.

Antigen receptor diversification in lymphocytes occurs not only during development in the primary lymphoid organs, but also as part of a complex response to exogenous stimuli delivered through the antigen receptor itself. In immature IgM+ bone marrow B cells, V(D)J recombination is reactivated in response to certain Ig receptor signals, leading to replacement of functionally rearranged Ig V regions. In this setting, receptor editing, as this process is known, may help prevent the emergence of autoreactive Ig specificities.70-73 Intensive diversification of Ig genes is also induced by antigen receptor signals in peripheral B cells during the germinal center reaction (Fig2). Germinal centers arise from a limited number of B cells activated by antigen and migrating to primary follicles, where they interact with follicular dendritic cells (FDC).74-76 After proliferative expansion, discrete dark and light zones are identified. The dark zone contains rapidly cycling centroblasts, whereas the light zone harbors resting centrocytes derived from the centroblasts, FDC that sequester antigen, and antigen-specific T cells and macrophages. Somatic hypermutation occurs in proliferating centroblasts. After exiting the cell cycle, progeny bearing mutated Ig genes migrate to the light zone, where interaction with antigen and FDC induces the survival of cells bearing high-affinity antigen receptors. Ig class switching occurs within the centrocyte compartment and is facilitated by interaction with T cells.77 Centrocytes selected by antigen may re-enter the dark zone and undergo further clonal expansion and somatic hypermutation or may exit the germinal center to differentiate into memory B cells or plasma cells.

Fig. 2.

The germinal center reaction. During immune responses, antigen-responsive B cells proliferate within lymphoid follicles, leading to formation of germinal centers. Rapidly cycling cells are located in the dark zone, where somatic hypermutation of Ig V regions occurs. Cells then exit the cell cycle and migrate to the light zone, where cell fates are determined by interaction with antigen-bearing FDC and antigen-specific T cells or undergo cell death. B cells with high-affinity receptors undergo class switch recombination and may either exit the germinal center to differentiate into memory cells and plasma cells or re-enter the dark zone for additional rounds of replication and hypermutation. Some B cells may also undergo V(D)J recombination.

Fig. 2.

The germinal center reaction. During immune responses, antigen-responsive B cells proliferate within lymphoid follicles, leading to formation of germinal centers. Rapidly cycling cells are located in the dark zone, where somatic hypermutation of Ig V regions occurs. Cells then exit the cell cycle and migrate to the light zone, where cell fates are determined by interaction with antigen-bearing FDC and antigen-specific T cells or undergo cell death. B cells with high-affinity receptors undergo class switch recombination and may either exit the germinal center to differentiate into memory cells and plasma cells or re-enter the dark zone for additional rounds of replication and hypermutation. Some B cells may also undergo V(D)J recombination.

Close modal

It was recently discovered that, in addition to somatic hypermutation and class switch recombination, germinal center B cells may also undergo receptor revision through V(D)J recombination. Thus, Rag-1 and Rag-2 are expressed in reactive germinal centers78,79 and mediate successive IgL rearrangements.80,81 Rearrangements of the IgH locus were also detected on the normal allele in mice with gene-targeted VDJ rearrangements of 1 allele.81 Recent studies cast doubt on the notion that Rag genes are re-expressed in Rag-negative mature B cells, and important questions remain regarding the origin of peripheral B-lineage cells undergoing V(D)J recombination in response to antigen signals.82,82a Both somatic hypermutation and receptor revision by V(D)J recombination have also been identified in peripheral T cells; however, their role in regulating the peripheral T-cell repertoire is not yet known.62 83 

Oncogene deregulation by control elements for antigen receptor gene expression.

A genetic hallmark of NHL is the presence of chromosome translocations involving the antigen receptor loci. Whereas oncogenic chromosome translocations commonly associated with most myeloid and some lymphoid leukemias result in the formation of a fusion gene and expression of a novel chimeric protein, NHL translocations typically place a structurally intact cellular proto-oncogene under the regulatory influence of the highly expressed Ig or TCR genes, leading to effects on cell growth, cell differentiation, or apoptosis.84-90The molecular structure of a number of recurrent translocations has been elucidated by breakpoint cloning and sequence analysis (Table 2). Of these, the role of the t(8;14) and t(14:18) translocations in the pathogenesis of lymphoma have been explored most thoroughly.

Table 2.

Examples of Recurrent Chromosome Translocations Involving Antigen Receptor Loci in Lymphoid Malignancies

graphic
 
graphic
 

For a more comprehensive listing, see Rabbitts88 and Mitelman et al.198 

Translocations involving c-myc are implicated in nearly all cases of Burkitt's lymphoma. Although these most often involve the IgH locus in t(8;14), variant translocations t(2;8)(p11;q24) and t(8;22)(q24;q11) are also observed, juxtaposing c-myc with the Igκ or Igλ loci, respectively.91-96 C-myc plays a broad role in transcriptional regulation of cell growth, differentiation and apoptosis (for reviews, see Henriksson and Luscher97 and Dang98). A role for t(8;14) in neoplasia was demonstrated by transgenic mice expressing c-myc under the control of the IgH intronic enhancer (Eμ) that exhibit polyclonal hyperplasia of pre-B cells and develop aggressive clonal B-lineage malignancies within several months.99-101 The t(14;18)(q32;q21), which is found in more than 85% of human follicular B-cell lymphomas, places the Bcl-2 gene in proximity to the IgH locus, usually directly upstream of one of the JH segments.85,102-105 Resulting Bcl-2 overexpression prolongs survival of B cells through inhibition of apoptosis.105-107 In Eμ-BCL2 transgenic mice, follicular B-cell hyperplasia is observed, with some mice eventually developing aggressive monoclonal B-cell lymphomas after a protracted latency period.107-109 These experiments demonstrate that deregulated expression of cellular proto-oncogenes by translocation into the IgH locus is sufficient to initiate an oncogenic pathway. Although there is a clear requirement for additional genetic changes for the development of lymphoma, these findings indicate that even very rare rearrangement events that involve antigen receptor loci have the potential to cause malignant disease.

Evidence implicating physiologic rearrangement processes.

The correlation between genetic instability of antigen receptor genes during lymphoid development and immune responses and lymphoid-specific oncogenic chromosome translocations involving the same loci yields a compelling hypothesis that NHL translocations arise from errors in these physiologic processes. The vast majority of V(D)J rearrangements occur on the same chromosome, even though the recombining sequences may be located megabases away. In principle, the V(D)J recombination mechanism is equally compatible with reciprocal rearrangements between chromosomes. A variety of interallelic and interlocus V(D)J rearrangements in lymphocytes have been described,110-113and these studies suggest that, although uncommon, recombination between chromosomes occurs physiologically at low frequency. Evidence for oncogenic translocations mediated by V(D)J recombinase is based on comparisons of translocation breakpoint sequences with normal antigen receptor rearrangements and is thus largely circumstantial (reviewed in Rabbitts,88 Tycko and Sklar,89 and Showe and Croce90). The t(14;18) translocations found in most cases of follicular B-cell lymphomas bear perhaps the strongest resemblance to normal V(D)J joints. Chromosome 14 breakpoints frequently occur at or near the RSS bordering DH or JH segments.85,102-105 In addition, sequences resembling the RSS heptamer have been described in proximity to breakpoints on 18q21.89,90,104 The t(7;9) (q34:q32) of T-cell lymphoblastic lymphoma/leukemia similarly involves breakpoints at RSS flanking D segments of the TCRβ gene on chromosome 7, whereas cleavage sites on chromosome 9 were flanked by consensus RSS heptamer sequences and separated from AT-rich nonamer-like sequences by an 11- to 12-bp motif.114 Also reminiscent of V(D)J coding joints is the frequent finding of nontemplated nucleotide additions suggestive of TdT activity at translocation breakpoints.89Despite the resemblance of some translocation breakpoints to V(D)J coding joints, much of the available data on breakpoint sequences do not strictly conform to the attributes of V(D)J recombination. Putative cryptic RSS are often located at some distance from the breakpoint or bear poor resemblance to physiologic RSS, including the critical heptamer sequence.89 In addition, precise determination of the initial cleavage sites requires analysis of the reciprocal translocation breakpoint. This has only been performed in a few studies, several of which indicate that cleavage did not occur at RSS borders.89 114-116 Taken together, the data available suggest that most chromosome translocations involving antigen receptor loci do not represent the products of normal V(D)J reactions.

An alternative scenario proposed for the involvement of V(D)J recombinase in chromosome translocation involves a hybrid mechanism, wherein physiologic DNA breaks within antigen receptor loci are rejoined with DNA breaks occurring elsewhere in the genome by other mechanisms.89 Nonantigen receptor breaks could occur randomly or could be targeted by particular features of the locus. For example, both the mbr and mcr breakpoint clusters accounting for most translocations involving the bcl-2 locus contain polypurine-polypyrimidine sequences similar to the Chi recombination element present in Escherichia coli.117,118 Binding of a 45-kD nuclear protein to the Chi-like sequences appears to facilitate their cleavage by a nuclease present in early B-cell extracts.118 Another potential rearrangement mechanism is suggested by recent studies of the Rag-1 and Rag-2 proteins, which bear a resemblance to prokaryotic transposases.119 120 After endonucleolytic cleavage at RSS, the Rag proteins remain complexed with signal ends, which may then engage in a nucleophilic attack on a DNA strand, leading to a transposition event. The second step appears to be sequence-independent and, therefore, could explain the absence of RSS on partner chromosomes involved in antigen receptor locus translocations. One or more of these mechanisms may lead to abnormal rejoining events involving DNA ends created during the V(D)J reaction.

Ig class switch recombination is implicated in t(8;14) in some cases of sporadic Burkitt's lymphoma, wherein the chromosome 14 breakpoints occur within the switch regions upstream of Cμ, Cγ, or Cα.116,121,122 Although such cases eliminate the Eμ enhancer on the der14 chromosome, it is now clear that the IgH locus contains other control elements. In particular, the 3′ Ig enhancer/locus control region located near Cα has potent long-range cis effects in deregulating c-myc expression.52 Switch recombination is also implicated in murine plasmacytomas occurring spontaneously or induced by pristane or mineral oil in susceptible strains.93,123-125 The majority of these tumors harbor t(12;15), juxtaposing c-myc with the switch α region on mouse chromosome 12. Recently, a novel oncogenic mechanism based on switch recombination has been identified in a multiple myeloma cell line. An excised switch region product containing Cα and the 3′ IgH enhancer were found inserted into chromosome 11 in close proximity to the cyclin D1 proto-oncogene, which is associated with cyclin D1 overexpression.126 This model widens the spectrum of potentially oncogenic recombination events that may occur during IgH switch recombination or, for that matter, during V(D)J recombination.

Somatic hypermutation of Ig variable regions has been found in most types of nodal B-cell lymphoma, suggesting that the precursors of these tumors have passed through a germinal center reaction.67,127 Given the recognition that DNA breaks accompany the hypermutation process, this diversification mechanism could potentially contribute directly to lymphoma-associated chromosome translocations.67-69 There is evidence that this may be the case in some t(8;14) Burkitt's lymphomas. Such translocations frequently involve a V(D)J rearranged IgH allele, and there are several examples of breakpoints occurring within the V region, correlating with the physiologic target of somatic hypermutation.67,127 In addition to a possible role in some Ig locus translocations, the somatic hypermutation process may introduce genetic alterations outside of the Ig loci. When placed near the Ig loci by a translocation, the c-myc and bcl-6 genes frequently develop point mutations characteristic of somatic hypermutation, potentially contributing to the additional genetic changes required for progression of the malignant phenotype.128,129 Recently, it was shown that somatic hypermutation also affects the germline bcl-6 gene in normal germinal center B cells, indicating that this process is not completely contained within the Ig loci under physiologic circum- stances.130-132 Altogether, peripheral B cells subjected to antigen stimulation may acquire DNA breaks by at least 3 distinct mechanisms. Each of these is potentially capable of being rejoined via alternative DNA damage repair mechanisms to generate chromosome translocations. Given the increased propensity for genetic errors in this tissue compartment, cellular surveillance mechanisms controlling DNA damage may be of particular importance in preventing oncogenic events.

Aside from immunodeficiency syndromes that impair host defenses against the Epstein-Barr virus, 3 inherited disorders in humans affect cellular responses to DNA damage and are associated with a high risk of lymphoid malignancies. As with tumor suppressor genes identified for other human cancers, the genes responsible for A-T, NBS, and Bloom's syndrome appear to function in pathways that monitor genomic integrity. These genes may therefore offer important clues to how neoplastic outcomes are prevented during antigen receptor diversification in lymphocytes. Candidate tumor-suppressor genes can be studied using mice, in which genetic manipulation may be combined with developmental and functional models of the immune system. These approaches are beginning to yield new models for the connection between genomic instability in lymphocytes and chromosome translocations in lymphoid malignancies.

A-T.

A-T is an autosomal recessive disorder characterized by progressive cerebellar ataxia, telangiectasias on sun-exposed surfaces, hypersensitivity to ionizing radiation, and cellular and humoral immunodeficiency (reviewed in Gatti133). The gene mutated in A-T, ATM, encodes a member of the PI-3 kinase gene family that includes the DNA-PKcs.134 Cancer affects approximately 38% of A-T patients, despite their reduced lifespans.133,135,136 Although adults may develop a broad array of solid tumors, 85% of malignancies in A-T patients are lymphoid leukemias and lymphomas. In children, these include ALL and lymphomas, predominantly of T-cell origin. Adults frequently develop chronic T-cell leukemias (T-PLL/T-CLL) associated with recurrent chromosome translocations involving the TCR α/δ, β, or γ loci and the TCL-1 oncogene on chromosome 14q32. Interestingly, up to half of the individuals without A-T who contract T-PLL are heterozygous carriers of mutations in the ATMgene.137-139 Loss of heterozygosity is observed for the normal allele in leukemic cells, suggesting that ATM functions as a classic tumor suppressor in this context.140 ATMmutations, as well as reduced ATM expression, have also been identified in a subset of B-CLL, suggesting that abnormalities in this gene may be involved in a diverse spectrum of lymphoid malignancies.141-143 

Susceptibility to lymphoid malignancies in A-T is paralleled by a general predisposition to chromosome translocations. Whereas fibroblasts exhibit increased but apparently random chromosomal rearrangement,144 a restricted set of translocations may be seen in up to 10% of nonmalignant lymphocytes from A-T patients.136 In some instances, these represent clonal T-cell expansions bearing translocations similar to those seen in T-PLL and are presumably premalignant. However, there is also a high frequency of translocations that are apparently not associated with oncogene activation and include V(D)J trans-rearrangements involving TCR loci on chromosomes 7 and 14.111,113 136 Such interlocus rearrangements can also be detected at a much lower frequency in normal individuals. These findings suggest that ATM is involved in limiting the number of interchromosomal rearrangements mediated by the V(D)J recombinase, a property that might explain the increased incidence of oncogenic translocations in A-T. It is striking that the chromosomal abnormalities in A-T lymphocytes primarily involve T cells, raising the possibility that the relative importance of various tumor-suppressor mechanisms differs for antigen receptor diversification in T versus B lymphocytes.

There is at present only a superficial understanding of how ATM functions in cells. A-T patients and cell lines exhibit heightened sensitivity to agents inducing double-strand DNA breaks such as ionizing radiation or bleomycin. In addition, A-T cells exhibit abnormal cell-cycle regulation in response to DNA damage. ATM does not appear to be directly involved in repairing DNA damage, inasmuch as extracts from A-T cells do not exhibit any consistent abnormalities in DNA repair proficiency.145 Similarly, a direct role for ATM in V(D)J recombination has been discounted based on normal rearrangement of plasmid recombination substrates in A-T fibroblasts.146 ATM has protein serine-threonine kinase activity, and a number of substrates have been identified in vitro and in vivo, many of which tend to play roles in either cell cycle checkpoint control or apoptotic pathways.147-150 In particular, ATM phosphorylates p53 in response to DNA breaks, and accumulation of p53 in response to DNA damage is delayed or absent in A-T cells. The emerging picture of ATM function, based both on clinical manifestations in A-T patients and biochemical characterization of ATM and its interacting partners, identifies ATM as playing a signaling role—receiving information from molecules that detect DNA damage, perhaps by direct binding to lesions, and relaying that information to appropriate downstream effector molecules that trigger responses ranging from cell cycle arrest to apoptosis. In this context, ATM could respond to unresolved DNA breaks during V(D)J recombination, either suppressing indiscriminate repair pathways or perhaps limiting the survival of cells at increased risk for abnormal rejoining events.

NBS.

NBS was first described in 1981 and was initially thought to be a clinical variant of A-T.151 NBS patients lack the characteristic ataxia and telangiectasias seen in A-T and instead are characterized by microcephaly, borderline mental retardation, and significant growth retardation. However, the disorders share several other features, including hypersensitivity to radiation, the characteristic chromosomal rearrangements in lymphocytes involving antigen receptor loci, and the predisposition toward malignancies, particularly those of lymphoid origin (reviewed in Wegner et al152). NBS is exceptionally rare, with fewer than 100 patients listed in the international NBS registry in Nijmegen. To date, 40% of these patients have developed a malignancy, of which 85% are leukemias or lymphomas. In contrast to the situation in A-T, the most common lymphoid tumors in NBS patients are NHL of B-cell origin.

The recent positional cloning of the NBS1 gene, which is mutated in the majority of NBS patients, clearly demonstrates that A-T and NBS are distinct disorders.153,154 The corresponding nibrin protein has no significant structural similarity to any other known protein. Biochemical studies show that nibrin forms part of a multiprotein complex that includes the products of the Rad50 and Mre11 genes and is distributed diffusely throughout the nucleus in fibroblasts.155 Irradiation of subnuclear regions leads to localization of these complexes to exposed regions where they form nuclear foci, a process that is defective in NBS cells.155,156 Mre11 has both a 3′ to 5′ exonuclease activity and a single-stranded endonuclease activity and is assumed to be directly involved in the repair of DNA damage.157 Among the substrates it can cleave are hairpins of the type formed after Rag-1/Rag-2–mediated cleavage,158,159 suggesting a potential role for the complex that includes nibrin in V(D)J recombination. Additional circumstantial evidence is provided by studies in yeast, in which repair of double-strand DNA breaks either by end ligation or nonhomologous end-joining requires the complex of Xrs2 (nibrin homologue)/Rad50/Mre11, as well as the Ku proteins.160Given the partial overlap in the clinical and cellular phenotypes between A-T and NBS, the relationship between the ATM and nibrin proteins in the cellular response to DNA damage remains a compelling question, the answer to which may be especially relevant to the pathogenesis of lymphoid malignancies.

Bloom's syndrome.

Bloom's syndrome is an autosomal recessive disorder characterized by growth retardation, erythemic telangiectasias in sun-exposed skin, defects in humoral immunity, and an extraordinary incidence of cancer. The disorder is associated with mutations in the BLM gene, which is homologous to ReqQ DNA helicases in bacteria.161 A recent report described 100 cancers arising in 71 of the 168 individuals from the Bloom's syndrome registry.162 These included a broad variety of tumors, occurring at a mean age of 25 years. The most common cancer in Bloom's syndrome is NHL, accounting for 21% of tumors in the registry, and the incidence of acute lymphoid leukemias is also markedly increased. Cells from Bloom's syndrome patients exhibit a mutator phenotype and are subject to chromosomal instability with a variety of spontaneous abnormalities, particularly those involving recombinational exchanges between homologous chromosomes.163-165 These abnormalities differ from those seen in A-T, and the extent to which antigen receptor loci may be affected is not known. The BLM gene does not appear to be directly involved in V(D)J recombination, which is normal in Bloom's syndrome fibroblasts using plasmid recombination assays.146Moreover, somatic hypermutation of Ig genes occurs at normal levels in lymphocytes from Bloom's syndrome patients.166 From the available information, it is not clear whether the increased incidence of lymphoid malignancies in Bloom's syndrome stems from abnormalities in antigen receptor diversification processes or simply reflects a general cellular defect in the maintenance of genomic integrity.

Susceptibility to lymphoma in gene-deficient mice.

Lymphomas arising spontaneously in genetically mutant strains of mice represent potentially important models for understanding the pathogenesis of lymphomas in humans. Unfortunately, the most common lymphoid malignancies in mice are thymic lymphomas, which are difficult to correlate with the major lymphoma subtypes afflicting man. Mice with a null mutation in p53 have a high incidence of lymphomas, occurring in up to two thirds of individuals.167,168 Although most are thymic tumors, peripheral B-cell lymphomas have also been reported. Mice with the Scid mutation affecting DNA-PKcs also have an increased incidence of thymic lymphomas compared with the parental strain, approaching 15% by 12 weeks of age in some colonies.169 Several groups have recently shown that mice with combined Scid and p53-null mutations (Scidp53−/−) develop disseminated B-lineage lymphomas, with incidence approaching 100% and occurring at a younger age than lymphoid tumors in either parental strain.170-172 Our group has shown that aggressive Scid p53−/− lymphomas carry a recurrent pattern of chromosome translocations involving the IgH locus near the telomere of chromosome 12.173 Chromosome 15 is the most common partner in these translocations. However, in contrast to the t(12;15) in murine mineral oil plasmacytomas, the c-myc oncogene does not lie on the derivative 12 chromosome, implying the involvement of a distinct oncogene in Scid p53−/− lymphomas. The tumors appear to arise at the pro-B–cell stage, coincident with physiologic IgH rearrangement, suggesting that the translocations arise during attempted IgH locus rearrangement inScid pro-B cells. This conclusion is supported by the finding that a Rag-2-null mutation blocked the development of t(12;15) pro-B–cell lymphomas when introduced into the Scidp53−/− strain, demonstrating that initiation of V(D)J recombination was a required element in the oncogenic pathway. Pro-B–cell lymphomas bearing t(12;15) have also been observed in Ku86−/− p53−/− mice (A. Nussenzweig, personal communication). Pro-B–cell lymphomas in Scidp53−/− mice appear to be pathogenetically distinct from the thymic lymphomas typical of p53−/− mice, which do not have a predominant cytogenetic marker173,174 and which occur with equivalent frequency in mice deficient in Rag-1 or Rag-2.173-175 

The predisposition to t(12;15) lymphomas conferred by combined mutations affecting DNA-PK and p53 function suggests that physiologic suppression of oncogenic DNA rearrangements during V(D)J recombination has 2 important elements: efficient rejoining of DNA ends created by Rag-mediated DNA scission and an intact cellular response to DNA damage (Fig 3). p53 is stabilized by posttranslational modification and accumulates rapidly in response to double-strand DNA breaks, leading to a broad cellular response that includes arrest of the cell cycle at the G1/S phase boundary and either DNA repair or apoptosis.176-178 In lymphocytes, the apoptotic response to p53 induction predominates.177,178Lymphoid precursors in Scid mice accumulate Rag-mediated DNA breaks within antigen receptor loci, which leads to activation of p53 and apoptosis.171,179,180 Impairment of the p53 DNA damage response in Scid p53−/− mice permits partial rescue of early thymocyte development, presumably because T-cell precursors survive long enough to undergo limited assembly of TCR genes by otherwise inefficient, DNA-PK–independent processes.170-172 By analogy, impairment of p53-dependent apoptosis in Scid pro-B cells may permit illegitimate rejoining of the cleaved IgH locus to chromosome 15 and other sites. p53 mutation could also contribute to the development of lymphoma by facilitating mutations elsewhere in the oncogenic pathway. In human lymphomas, mutation of p53 is not a consistent finding, being primarily associated with aggressive subtypes and with relapse, suggesting that it may occur late in malignant evolution.181-183 Moreover, lymphoid malignancies are not prominent among tumors in patients with Li-Fraumeni syndrome, who carry germline p53 mutations.184-186 Given the complexity of the cellular response to DNA damage, it may be that the functions of other genes involved in these pathways are more relevant to containing lymphoid-specific mechanisms of genomic instability.

Fig. 3.

Model for susceptibility to chromosome translocations mediated by V(D)J recombinase. Antigen receptor diversification is initiated by DNA breaks, mediated in the case of V(D)J recombination by the Rag-1 and Rag-2 proteins at RSS-coding segment borders (depicted by triangles and squares, respectively). The normal rejoining process resolves both sets of DNA ends efficiently, so that the potential for aberrant recombination is minimal. Failure of the normal rejoining process triggers cellular DNA damage sensors, which effect cell death and thereby prevent oncogenic rearrangements. Impairment in cellular DNA damage responses may allow alternative DNA repair pathways to mediate rejoining of antigen receptor genes with sites elsewhere in the genome—sometimes including oncogene loci, which give rise to lymphoma-associated chromosome translocations.

Fig. 3.

Model for susceptibility to chromosome translocations mediated by V(D)J recombinase. Antigen receptor diversification is initiated by DNA breaks, mediated in the case of V(D)J recombination by the Rag-1 and Rag-2 proteins at RSS-coding segment borders (depicted by triangles and squares, respectively). The normal rejoining process resolves both sets of DNA ends efficiently, so that the potential for aberrant recombination is minimal. Failure of the normal rejoining process triggers cellular DNA damage sensors, which effect cell death and thereby prevent oncogenic rearrangements. Impairment in cellular DNA damage responses may allow alternative DNA repair pathways to mediate rejoining of antigen receptor genes with sites elsewhere in the genome—sometimes including oncogene loci, which give rise to lymphoma-associated chromosome translocations.

Close modal

A number of other mouse strains with defects in V(D)J recombination and/or DNA damage responses exhibit susceptibility to lymphomas. In particular, mice lacking Atm have a high incidence of thymic lymphomas. Cytogenetic studies indicate that these tumors carry complex karyotypic abnormalities, including translocations involving chromosome 14, which harbors the mouse TCRα/δ complex.187,188 The proximity of the TCR loci to the translocation breakpoints in these tumors has not been reported. T-lymphoid malignancies are also increased in mice with mutations in the V(D)J recombinase component Ku70,31,189 combined Scid and PARP-null mutations,190 as well as mice deficient in the DNA mismatch repair gene MSH2.191-193 Cytogenetic studies, which have provided seminal insights into the pathogenesis of lymphoid malignancies in humans, have received limited application in mouse lymphoid tumors. Although this undoubtedly reflects the challenges inherent in the interpretation of mouse karyotypes, techniques such as spectral karyotyping188 or panels of chromosome-specific probes194 may facilitate a more detailed characterization of lymphoid malignancies associated with specific genetic defects in mice.

The capability of the immune system to recognize new pathogens and mount adaptive responses depends on the creation of antigen receptor gene diversity through the induction of targeted genomic instability. In addition to ordered rearrangements during B- and T-cell ontogeny, changes in the genetic makeup of lymphoid cells occur through reflexive interactions with antigenic selection mechanisms, leading to rapid evolution of the immune repertoire. Escape of these gene diversification processes from their physiologic targets remains a compelling explanation for many of the oncogenic genetic alterations that are unique to malignancies of the lymphoid lineage. From the standpoint of cancer biology, the genetic instability required for adaptive immunity appears to violate fundamental cellular paradigms for maintaining integrity of the genome. As the mechanisms of antigen receptor gene diversification are elucidated, it is thus important to ask how these processes are contained and targeted specifically to their intended loci. Measures to ensure genetic safety could operate at 3 levels: by regulating specificity in the targeting of DNA breaks, by monitoring the resultant DNA ends and facilitating appropriate rejoining mechanisms, and by preventing indiscriminate DNA repair.

For V(D)J recombination, 2 features of the cleavage reaction may contribute to specificity. Recognition of RSS by Rag-1 and Rag-2 defines the correct sites for DNA breaks. However, the sequence requirements observed during in vitro cleavage reactions are more degenerate than observed in vivo,5 suggesting that other factors may assist in directing DNA scission to the appropriate target. Such factors may be tied to the regulation of V(D)J rearrangement by transcription. Specificity is also enhanced by the preferential rearrangement of segments located on the same chromosome, even though RSS pairs may be located megabases apart. In experiments using extrachromosomal recombination substrates, a similar bias is seen for intramolecular over intermolecular reactions, with a recent study indicating that this bias occurs at the level of coding end rejoining.195 If these results can be extrapolated to chromosomal loci, they may shed light on an important mechanism for suppressing chromosome translocation events. Cellular exposure to free DNA ends during the V(D)J reaction is controlled in part by the obligate coupling of 2 cleavage events. These occur within a single synaptic complex that facilitates efficient rejoining.8Similar principles may apply to class switch recombination, which, like V(D)J recombination, involves reciprocal rejoining of ends and requires the DNA-PK complex. Rejoining of antigen receptor DNA breaks by DNA-PK–independent processes appears to entail a lesser degree of protection for cut ends, and exclusion of indiscriminate DNA repair may be an important factor in preventing aberrant rejoining events. For example, Rag-mediated DNA cleavage is restricted to the G0/G1 phases of the cell cycle,196 a feature that may preclude replication-dependent repair of unresolved DNA ends. Measures to ensure precise targeting and rapid resolution of DNA breaks during antigen receptor diversification may occasionally fail, necessitating cellular responses that either interrupt the propagation of cells susceptible to abnormal recombination events or otherwise prevent inappropriate rejoining. Indeed, compared with other somatic cells, lymphocytes have a low threshold for death after DNA damage, which may reflect an adaptation to the oncogenic risks inherent in antigen receptor diversification. In mice, the p53 pathway acts as a tumor suppressor for lymphoid malignancies and is particularly important when rejoining of V(D)J-mediated DNA breaks is impaired—a point underscored by the high incidence of lymphomas harboring recurrent chromosome translocations observed in mice with combined mutations in DNA-PKcs and p53. In humans, ATM could serve a related function by activating p53 and other cellular responses to unresolved DNA breaks in antigen receptor genes. Further studies of ATM and other lymphoma susceptibility genes will provide additional insight into these pathways.

The germinal center has emerged as a focal point for investigating the pathogenesis of lymphoid malignancies, particularly B-cell NHL. In physiologic terms, the germinal center is a veritable hotbed of genomic instability, in which the iterative process of antigen receptor gene mutation, selection, and proliferation leads to a rapid evolutionary improvement in Ig affinity for antigen. This involves both gradualistic changes, ie, accumulations of small mutations, as well as saltations engendered by wholesale replacement of V regions. At the same time, exchange of IgH constant regions through class switch recombination broadens the effector functions of antibodies. The common subtypes of nodal B-cell NHL resemble normal components of the germinal center, and successive pathological classification schemes have built on improving knowledge of the presumed normal cellular counterparts.197The most prevalent types of B-cell lymphomas have also been shown to harbor somatic mutations of Ig V regions, further supporting the notion that the critical genetic event leading to clonal growth occurred during or after a germinal center reaction (reviewed in Klein et al127). The recent picture of genomic instability in the germinal center raises the possibility that oncogenic translocations may arise in mature B cells by DNA breaks induced during V(D)J recombination and other diversification processes in the course of immune responses. In this regard, the recognition that genomic instability in lymphocytes is regulated by antigen receptor signals raises the possibility that disordered immunity could enhance the risk of aberrant recombination events. This could account for the association between certain lymphoma types and chronic immune stimulation, as well as the high incidence of lymphomas in AIDS.

Studies of the chromosomal alterations found in lymphoid malignancies have provided seminal insights into the molecular basis for neoplasia in this lineage. Recent advances in understanding the genetic, molecular, and biochemical basis for antigen receptor diversification open new avenues for investigating pathways that underlie predisposition to oncogenic chromosomal rearrangements. Such progress may ultimately lead to a clearer understanding of the causes of lymphoid malignancies.

The authors acknowledge the many valuable contributions by investigators whose work, owing to space limitations, was not cited directly in this review. We are grateful to Dr Garnett Kelsoe for helpful discussions during the preparation of the manuscript.

Supported in part by National Institutes of Health Grants No. HL07093, CA57569, and the Royalty Research fund of the University of Washington.

1
Alt
FW
Oltz
EM
Young
F
Gorman
J
Taccioli
G
Chen
J
VDJ recombination.
Immunol Today
13
1992
313
2
Willerford
DM
Swat
W
Alt
FW
Developmental regulation of V(D)J recombination and lymphocyte differentiation.
Curr Opin Genet Dev
6
1996
603
3
Oettinger
MA
Schatz
DG
Gorka
C
Baltimore
DG
RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination.
Science
248
1990
1517
4
van Gent
DC
McBlane
JF
Ramsden
DA
Sadofsky
MJ
Hesse
JE
Gellert
M
Initiation of V(D)J recombination in a cell-free system.
Cell
81
1995
925
5
McBlane
JF
van Gent
DC
Ramsden
DA
Romeo
C
Cuomo
CA
Oettinger
MA
Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps.
Cell
83
1995
387
6
Eastman
QM
Leu
TM
Schatz
DG
Intitiation of V(D)J recombination in vitro obeying the 12/23 rule.
Nature
380
1996
85
7
van Gent
DC
Ramsden
DA
Gellert
M
The Rag-1 and Rag-2 proteins establish the 12/23 rule in V(D)J recombination.
Cell
85
1996
107
8
Hiom
K
Gellert
M
Assembly of a 12/23 paired signal complex: A critical control point in V(D)J recombination.
Mol Cell
1
1998
1011
9
Shinkai
Y
Rathbun
G
Lam
KP
M. Oltz
EM
Stewart
V
Mendelsohn
M
Charron
J
Datta
M
Young
F
Stall
AM
Alt
FW
RAG-2 deficient mice lack mature lymphocytes owing to inability to initate V(D)J rearrangement.
Cell
68
1992
855
10
Mombaerts
P
Iacomini
J
Johnson
RS
Herrup
K
Tonegawa
S
Papaioannou
VE
RAG-1 deficient mice have no mature B and T lymphocytes.
Cell
68
1992
869
11
Schwartz
K
Gauss
GH
Ludwig
L
Pannicke
U
Li
Z
Lindner
D
Friedrich
W
Seger
RA
Hansen-Hagge
TE
Desiderio
S
Lieber
MR
Bartram
CR
RAG mutations in human B cell-negative SCID.
Science
274
1996
97
12
Villa
A
Santagata
S
Bozzi
F
Giliani
S
Frattini
A
Imberti
L
Gatta
LB
Ochs
HD
Schwarz
K
Notarangelo
LD
Vezzoni
P
Spanopoulou
E
Partial V(D)J recombination activity leads to Omenn syndrome.
Cell
93
1998
885
13
Taccioli
GE
Rathbun
G
Oltz
E
Stamato
T
Jeggo
PA
Alt
FW
Impairment of V(D)J recombination in double-strand break repair mutants.
Science
260
1993
207
14
Taccioli
GE
Alt
FW
Potential targets for autosomal SCID mutations.
Curr Opin Immunol
7
1992
436
15
Shimizu
T
Iwasato
T
Yamagishi
H
Deletions of immunoglobulin C kappa region characterized by the circular excision products in mouse splenocytes.
J Exp Med
173
1991
1065
16
Roth
DB
Lindahl
T
Gellert
M
Repair and recombination. How to make ends meet.
Curr Biol
5
1995
496
17
Gottlieb
TM
Jackson
SP
The DNA-dependent protein kinase: Requirement for DNA ends and association with Ku antigen.
Cell
72
1993
131
18
Hartley
KO
Gell
D
Smith
GC
Zhang
H
Divecha
N
Connelly
MA
Admon
A
Lees-Miller
SP
Anderson
CW
Jackson
SP
DNA-dependent protein kinase catalytic subunit: A relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product.
Cell
82
1995
849
19
Blunt
T
Finnie
NJ
Taccioli
GE
Smith
GC
Demengeot
J
Gottleib
TM
Mizuta
R
Varghese
AJ
Alt
FW
Jeggo
PA
Jackson
S
Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation.
Cell
80
1995
813
20
Kirchgessner
CU
Patil
CK
Evans
JW
Cuomo
CA
Fried
LM
Carter
T
Oettinger
MA
Brown
JM
DNA-dependent protein kinase (p350) as a candidate gene for the murine SCID defect.
Science
267
1995
1178
21
Gao
Y
Chaudhuri
J
Zhu
C
Davidson
L
Weaver
DT
Alt
FW
A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination.
Immunity
9
1998
367
22
Taccioli
GT
Amatucci
AG
Beamish
HJ
Gell
D
Xiang
CH
Arzayus
MIT
Priestley
A
Jackson
SP
Rothstein
AM
Jeggo
PA
Herrera
VLM
Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severer combined immunodeficiency and radiosensitivity.
Immunity
9
1998
355
23
Bogue
MA
Jhappan
C
Roth
DB
Analysis of variable (diversity) joining recombination in DNAdependent protein kinase (DNA-PK)-deficient mice reveals DNA-PK-independent pathways for both signal and coding joint formation.
Proc Natl Acad Sci USA
95
1998
15559
24
Lieber
MR
Hesse
JE
Lewis
S
Bosma
GC
Rosenberg
N
Mizuuchi
K
Bosma
MJ
Gellert
M
The defect in murine severe combined immune deficiency: Joining of signal sequences but not coding segments in V(D)J recombination.
Cell
55
1988
7
25
Malynn
BA
Blackwell
TK
Fulop
GM
Rathbun
GA
Furley
AJW
Ferrier
P
Heinke
LB
Phillips
RA
Yancopoulos
GD
Alt
FW
The scid defect affects the final step of the immunoglobulin VDJ recombinase mechanism.
Cell
54
1988
453
26
Smider
V
Rathmell
WK
Lieber
MR
Chu
G
Restoration of x-ray resistance and V(D)J recombination in mutant cells by Ku cDNA.
Science
266
1994
288
27
Gu
Y
Jin
S
Gao
Y
Weaver
DT
Alt
FW
Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination.
Proc Natl Acad Sci USA
94
1997
8076
28
Zhu
C
Bogue
MA
Lim
D-S
Hasty
P
Roth
DB
Ku86-deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates.
Cell
86
1996
379
29
Nussenzweig
A
Chen
C
da Costa Soares
V
Sanchez
M
Sokol
K
Nussenzweig
MC
Li
GC
Requrement for Ku80 in growth and immunoglobulin V(D)J recombination.
Nature
382
1996
551
30
Ouyang
H
Nussenzweig
A
Kurimasa
A
Soares
VC
Li
X
Cordon-Cardo
C
Li
W
Cheong
N
Nussenzweig
M
Iliakis
G
Chen
DJ
Li
GC
Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo.
J Exp Med
186
1997
921
31
Gu
Y
Seidl
K
Rathbun
GA
Zhu
C
Manis
JP
van der Stoep
N
Davidson
L
Cheng
H-L
Skiguchi
JM
Frank
K
Stanhope-Baker
P
Schlissel
MS
Roth
DB
Alt
FW
Growth retardation and leaky scid phenotype of Ku70-deficient mice.
Immunity
7
1997
653
32
Li
Z
Otevrel
T
Gao
Y
Cheng
HL
Seed
B
Stamato
TD
Taccioli
GE
Alt
FW
The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination.
Cell
83
1995
1079
33
Grawunder
U
Zimmer
D
Fugmann
S
Schwarz
K
Lieber
MR
DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes.
Mol Cell
2
1998
477
34
Grawunder
U
Wilm
M
Wu
X
Kulesza
P
Wilson
TE
Mann
M
Lieber
MR
Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells.
Nature
388
1997
492
35
Critchlow
SE
Bowater
RP
Jackson
SP
Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV.
Curr Biol
7
1997
588
36
Frank
KM
Sekiguchi
JM
Seidl
KJ
Swat
W
Rathbun
GA
Cheng
HL
Davidson
L
Kangaloo
L
Alt
FW
Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV.
Nature
396
1998
173
37
Gao
Y
Sun
Y
Frank
KM
Dikkes
P
Fujiwara
Y
Seidl
KJ
Sekiguchi
JM
Rathbun
GA
Swat
W
Wang
J
Bronson
RT
Malynn
BA
Bryans
M
Zhu
C
Chaudhuri
J
Davidson
L
Ferrini
R
Stamato
T
Orkin
SH
Greenberg
ME
Alt
FW
A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis.
Cell
95
1998
891
38
Wu
Q
Maniatis
T
A striking organization of a large family of human neural cadherin-like cell adhesion genes.
Cell
97
1999
779
39
Sleckman
BP
Gorman
J
Alt
FW
Accessibility control of antigen-receptor variable-region gene assembly: Role of cis-acting elements.
Annu Rev Immunol
14
1996
459
40
Stanhope-Baker
P
Hudson
KM
Shaffer
AL
Constantinescu
A
Schlissel
MS
Cell type-specific chromatin structure determines the targeting of V(D)J recombinase activity in vitro.
Cell
85
1996
887
41
Villey
I
Caillol
D
Selz
F
Ferrier
P
de Villartay
J-P
Defect in rearrangement of the most 5′ TCR-Jα following targeted deletion of T early α (TEA): Implications for TCR α locus accessibility.
Immunity
5
1996
331
42
Whitehurst
CJ
Chattopadhyay
S
Chen
J
Control of V(D)J recombinational acessibility of the Dβ1 gene segment at the TCRβ locus by a germline promoter.
Immunity
10
1999
313
43
Stavnezer
J
Antibody class switching.
Adv Immunol
61
1996
79
44
Iwasato
T
Shimizu
A
Honjo
T
Yamagishi
H
Circular DNA is excised by immunoglobulin class switch recombination.
Cell
62
1990
143
45
Kinoshita
K
Tashiro
J
Tomita
S
Lee
CG
Honjo
T
Target specificity of immunoglobulin class switch recombination is not determined by nucleotide sequences of S regions.
Immunity
9
1998
849
46
Stavnezer
J
Immunoglobulin class switching.
Curr Opin Immunol
8
1996
199
47
Rolink
A
Melchers
F
Andersson
J
The SCID but not the RAG-2 gene product is required for S mu-S epsilon heavy chain class switching.
Immunity
5
1996
319
48
Lansford
R
Manis
JP
Sonoda
E
Rajewsky
K
Alt
FW
Ig heavy chain class switching in Rag-deficient mice.
Int Immunol
10
1998
325
49
Snapper
CM
Marcu
KB
Zelazowski
P
The immunoglobulin class switch: Beyond “accessibility.”
Immunity
6
1997
217
50
Cogne
M
Lansford
R
Bottaro
A
Zhang
J
Gorman
J
Young
F
Cheng
HL
Alt
FW
A class switch control region at the 3′ end of the immunoglobulin heavy chain locus.
Cell
77
1994
737
51
Manis
JP
van der Stoep
N
Tian
M
Ferrini
R
Davidson
L
Bottaro
A
Alt
FW
Class switching in B cells lacking 3′ immunoglobulin heavy chain enhancers.
J Exp Med
188
1998
1421
52
Madisen
L
Groudine
M
Identification of a locus control region in the immunoglobulin heavy-chain locus that deregulates c-myc expression in plasmacytoma and Burkitt's lymphoma cells.
Genes Dev
8
1994
2212
53
Jung
S
Rajewsky
K
Radbruch
A
Shutdown of class switch recombination by deletion of a switch region control element.
Science
259
1993
984
54
Zhang
J
Bottaro
A
Li
S
Stewart
V
Alt
FW
A selective defect in IgG2b switching as a result of targeted mutation of the I gamma 2b promoter and exon.
EMBO J
12
1993
3529
55
Bottaro
A
Lansford
R
Xu
L
Zhang
J
Rothman
P
Alt
FW
S region transcription per se promotes basal IgE class switch recombination but additional factors regulate the efficiency of the process.
EMBO J
13
1994
665
56
Lorenz
M
Jung
S
Radbruch
A
Switch transcripts in immunoglobulin class switching.
Science
267
1995
1825
57
Hein
K
Lorenz
MG
Siebenkotten
G
Petry
K
Christine
R
Radbruch
A
Processing of switch transcripts is required for targeting of antibody class switch recombination.
J Exp Med
188
1998
2369
58
Manis
JP
Gu
Y
Lansford
R
Sonoda
E
Ferrini
R
Davidson
L
Rajewsky
K
Alt
FW
Ku70 is required for late B cell development and immunoglobulin heavy chain class switching.
J Exp Med
187
1998
2081
59
Casellas
R
Nussenzweig
A
Wuerffel
R
Pelanda
R
Reichlin
A
Suh
H
Qin
XF
Besmer
E
Kenter
A
Rajewsky
K
Nussenzweig
MC
Ku80 is required for immunoglobulin isotype switching.
EMBO J
17
1998
2404
60
Neuberger
MS
Milstein
C
Somatic hypermutation.
Curr Opin Immunol
7
1995
248
61
Storb
U
The molecular basis of somatic hypermutation of immunoglobulin genes.
Curr Opin Immunol
8
1996
206
62
Storb
U
Progress in understanding the mechanism and consequences of somatic hypermutation.
Immunol Rev
162
1998
5
63
Kim
M
Storb
U
The role of DNA repair in somatic hypermutation of immunoglobulin genes.
J Exp Med
187
1998
1729
64
Wood
RD
DNA repair: Knockouts still mutating after first round.
Curr Biol
8
1998
R757
65
Kelsoe
G
V(D)J hypermutation and DNA mismatch repair: Vexed by fixation.
Proc Natl Acad Sci USA
95
1998
6576
66
Vora
KA
Tumas-Brundage
KM
Lentz
VM
Cranston
A
Fishel
R
Manser
T
Severe attenuation of the B cell immune response in Msh2-deficient mice.
J Exp Med
189
1999
471
67
Goossens
T
Klein
U
Kuppers
R
Frequent occurrence of deletions and duplications during somatic hypermutation: Implications for oncogene translocations and heavy chain disease.
Proc Natl Acad Sci USA
95
1998
2463
68
Wilson
PC
de Bouteiller
O
Liu
YJ
Potter
K
Banchereau
J
Capra
JD
Pascual
V
Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes.
J Exp Med
187
1998
59
69
Sale
JE
Neuberger
MS
TdT-accessible breaks are scattered over the immunoglobulin V domain inn a constitutively hypermutating B cell line.
Immunity
9
1998
859
70
Radic
MZ
Zouali
M
Receptor editing, immune diversification, and self-tolerance.
Immunity
5
1996
505
71
Nussenzweig
MC
Immune receptor editing: Revise and select.
Cell
95
1998
875
72
Chen
C
Nagy
Z
Prak
EL
Weigert
M
Immunoglobulin heavy chain gene replacement: A mechanism of receptor editing.
Immunity
3
1995
747
73
Chen
C
Prak
EL
Weigert
M
Editing disease-associated autoantibodies.
Immunity
6
1997
97
74
Jacob
J
Kelsoe
G
Rajewsky
K
Weiss
U
Intraclonal generation of antibody mutants in germinal centres.
Nature
354
1991
389
75
Liu
YJ
Arpin
C
Germinal center development.
Immunol Rev
156
1997
111
76
MacLennan
IC
Liu
YJ
Johnson
GD
Maturation and dispersal of B-cell clones during T cell-dependent antibody responses.
Immunol Rev
126
1992
143
77
Liu
YJ
Malisan
F
de Bouteiller
O
Guret
C
Lebecque
S
Banchereau
J
Mills
FC
Max
EE
Martinez-Valdez
H
Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation.
Immunity
4
1996
241
78
Han
S
Zheng
B
Schatz
DG
Spanopoulou
E
Kelsoe
G
Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells.
Science
274
1996
2094
79
Hikida
M
Mori
M
Takai
T
Tomochika
K
Hamatani
K
Ohmori
H
Reexpression of Rag-1 and Rag-2 genes in activated mature mouse B cells.
Science
274
1996
2092
80
Han
S
Dillon
SR
Zheng
B
Shimoda
M
Schlissel
MS
Kelsoe
G
V(D)J recombinase activity in a subset of germinal center B lymphocytes.
Science
278
1997
301
81
Papavasiliou
F
Casellas
R
Suh
H
Qin
X-F
Besmer
E
Pelanda
R
Nemazee
D
Rajewsky
K
Nussenzweig
MC
V(D)J recombination in mature B cells: A mechanism for altering antibody responses.
Science
278
1997
298
82
Yu
W
Nagaoka
H
Jankovic
M
Misulorin
Z
Suh
H
Rulink
A
Melchers
F
Meltre
E
Nussenzweg
MC
Continued RAG expression in late stages of B cell development and no apparent reinduction after immunization.
Nature
400
1999
682
82a
Monroe
RJ
Seidl
KJ
Gaertner
F
Han
S
Sekiguchi
J
Wang
J
Ferrini
R
Davidson
L
Kelsoc
G
Alt
FW
Rag 2: GFP knockin mice reveal novel aspects of Rag2 expression in primary and peripheral lymphoid tissues.
Immunity
11
1999
201
83
McMahan
CJ
Fink
PJ
RAG reexpression and DNA recombination at T cell receptor loci in peripheral CD4+ T cells.
Immunity
9
1998
637
84
Drexler
HG
MacLeod
RAF
Borkhardt
A
Janssen
JWG
Recurrent chromosomal translocations and fusion genes in leukemia-lymphoma cell lines.
Leukemia
9
1995
480
85
Finger
LR
Harvey
RC
Moore
RCA
Showe
LC
Croce
CM
A common michanism of chromosomal translocation in T- and B-cell neoplasia.
Science
234
1986
982
86
Korsmeyer
SJ
Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes.
Annu Rev Immunol
10
1992
785
87
Magrath
I
Molecular basis of lymphomagenesis.
Cancer Res
52
1992
5529s
88
Rabbitts
TH
Chromosomal translocations in human cancer.
Nature
372
1994
143
89
Tycko
B
Sklar
J
Chromosomal translocations in lymphoid neoplasia: A reappraisal of the recombinase model.
Cancer Cells
2
1990
1
90
Showe
LC
Croce
CM
The role of chromosomal translocations in B- and T-cell neoplasia.
Annu Rev Immunol
5
1987
253
91
Adams
JM
Gerondakis
S
Webb
E
Corcoran
LM
Cory
S
Cellular myc oncogene is altered by chromosome translocation to an immunoglobulin locus in murine plasmacytomas and is rearranged similarly in human Burkitt lymphomas.
Proc Natl Acad Sci USA
80
1983
1982
92
Dalla-Favera
R
Bregni
M
Erikson
J
Patterson
D
Gallo
RC
Croce
CM
Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells.
Proc Natl Acad Sci USA
79
1982
7824
93
Taub
R
Kirsch
I
Morton
C
Lenoir
G
Swan
D
Tronick
S
Aaronson
S
Leder
P
Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells.
Proc Natl Acad Sci USA
79
1982
7837
94
Erikson
J
Nishikura
K
ar-Rushdi
A
Finan
J
Emanuel
B
Lenoir
G
Nowell
PC
Croce
CM
Translocation of an immunoglobulin kappa locus to a region 3′ of an unrearranged c-myc oncogene enhances c-myc transcription.
Proc Natl Acad Sci USA
80
1983
7581
95
Hollis
GF
Mitchell
KF
Battey
J
Potter
H
Taub
R
Lenoir
GM
Leder
P
A variant translocation places the lambda immunoglobulin genes 3′ to the c-myc oncogene in Burkitt's lymphoma.
Nature
307
1984
752
96
Lenoir
GM
Preud'homme
JL
Bernheim
A
Berger
R
Correlation between immunoglobulin light chain expression and variant translocation in Burkitt's lymphoma.
Nature
298
1982
474
97
Henriksson
M
Luscher
B
Proteins of the Myc network: Essential regulators of cell growth and differentiation.
Adv Cancer Res
68
1996
109
98
Dang
CV
c-Myc target genes involved in cell growth, apoptosis, and metabolism.
Mol Cell Biol
19
1999
1
99
Adams
JM
Harris
AW
Pinkert
CC
Corcoran
LM
Alexander
WS
Cory
S
Palmiter
RD
Brinster
RL
The c-myc oncogene driven by immunoglobulin enhancers induced lymphoid malignancies in transgenic mice.
Nature
318
1985
533
100
Langdon
WY
Harris
AW
Cory
S
Adams
JM
The c-myc oncogene perturbs B lymphocyte development in E-mu-myc transgenic mice.
Cell
47
1986
11
101
Leder
A
Pattengale
PK
Kuo
A
Stewart
TA
Leder
P
Consequences of widespread deregulation of the c-myc gene in transgenic mice: Multiple neoplasms and normal development.
Cell
45
1986
485
102
Bakhshi
A
Jensen
JP
Goldman
P
Wright
JJ
McBride
OW
Epstein
AL
Korsmeyer
SJ
Cloning the chromosomal breakpoint of t(14;18) human lymphomas: Clustering around JH on chromosome 14 and near a transcriptional unit on 18.
Cell
41
1985
899
103
Cleary
ML
Sklar
J
Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint cluster region near a transcriptionally active locus on chromosome 18.
Proc Natl Acad Sci USA
82
1985
7439
104
Tsujimoto
Y
Gorham
J
Cossman
J
Jaffe
E
Croce
CM
The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining.
Science
22
1985
1390
105
Yang
E
Korsmeyer
SJ
Molecular thanatopsis: A discourse on the BCL2 family and cell death.
Blood
88
1996
386
106
Vaux
DL
Cory
S
Adams
JM
Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells.
Nature
335
1988
440
107
McDonnell
TJ
Deane
N
Platt
FM
Nunez
G
Haeger
U
McKearn
JP
Korsmeyer
SJ
bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation.
Cell
57
1989
79
108
McDonnell
TJ
Korsmeyer
SJ
Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14:18).
Nature
349
1991
254
109
Strasser
A
Harris
AW
Cory
S
Eμ-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin secreting cells but not T cells.
Oncogene
8
1993
1
110
Tycko
B
Palmer
JD
Sklar
J
T cell receptor gene trans-rearrangements: Chimeric γ-δ genes in normal lymphoid tissues.
Science
245
1989
1242
111
Lipkowitz
S
Stern
M-H
Kirsch
IR
Hybrid T cell receptor genes formed by interlocus recombination in normal and Ataxia-telangiectasia lymphocytes.
J Exp Med
172
1990
409
112
Aster
JC
Sklar
J
Interallelic V(D)J trans-rearrangement within the beta T cell receptor gene is infrequent and occurs preferentially during attempted D beta to J beta joining.
J Exp Med
175
1992
1773
113
Kobayashi
Y
Tycko
B
Soreng
AL
Sklar
J
Transrearrangements between antigen receptor genes in normal human lymphoid tissues and in ataxia telangiectasia.
J Immunol
147
1991
3201
114
Tycko
B
Reynolds
TC
Smith
SD
Sklar
J
Consistent breakage between consensus recombinase heptamers of chromosome 9 DNA in a recurrent chromosomal translocation of human T cell leukemia.
J Exp Med
169
1989
369
115
Bakhshi
A
Wright
JJ
Graninger
W
Seto
M
Owens
J
Cossman
J
Jensen
JP
Goldman
P
Korsmeyer
SJ
Mechanism of the t(14;18) chromosomal translocation: Structural analysis of both derivative 14 and 18 reciprocal partners.
Proc Natl Acad Sci USA
84
1987
2396
116
Neri
A
Barriga
F
Knowles
DM
Magrath
IT
Dalla-Favera
R
Different regions of the immunoglobulin heavy-chain locus are involved in chromosomal translocations in distinct pathogenetic forms of Burkitt lymphoma.
Proc Natl Acad Sci USA
85
1988
2748
117
Wyatt
RT
Rudders
RA
Zelenetz
A
Delellis
RA
Krontiris
TG
BCL2 oncogene translocation is mediated by a chi-like consensus.
J Exp Med
175
1992
1575
118
Jaeger
U
Purtscher
B
Delle Karth
G
Knap
S
Mannhalter
C
Lechner
K
Mechanism of the chromosomal translocation t(14:18) in lymphoma: Detection of a 45-Kd breakpoint binding protein.
Blood
81
1993
1833
119
Agrawal
A
Eastman
QM
Schatz
DG
Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system.
Nature
394
1998
744
120
Hiom
K
Melek
M
Gellert
M
DNA transposition by the RAG1 and RAG2 proteins: A possible source of oncogenic translocations.
Cell
94
1998
463
121
Gutierrez
MI
Bhatia
K
Barriga
F
Diez
B
Muriel
FS
de Andreas
ML
Epelman
S
Risueno
C
Magrath
IT
Molecular epidemiology of Burkitt's lymphoma from South America: Differences in breakpoint location and Epstein-Barr virus association from tumors in other world regions.
Blood
79
1992
3261
122
Shiramizu
B
Barriga
F
Neequaye
J
Jafri
A
Dalla-Favera
R
Neri
A
Guttierez
M
Levine
P
Magrath
I
Patterns of chromosomal breakpoint locations in Burkitt's lymphoma: Relevance to geography and Epstein-Barr virus association.
Blood
77
1991
1516
123
Cory
S
Gerondakis
S
Adams
JM
Interchromosomal recombination of the cellular oncogene c-myc with the immunoglobulin heavy chain locus in murine plasmacytomas is a reciprocal exchange.
EMBO J
2
1983
697
124
Gerondakis
S
Cory
S
Adams
JM
Translocation of the myc cellular oncogene to the immunoglobulin heavy chain locus in murine plasmacytomas is an imprecise reciprocal exchange.
Cell
36
1984
973
125
Potter
M
Experimental plasmacytomagenesis in mice.
Hematol Oncol Clin North Am
11
1997
323
126
Gabrea
A
Bergsagel
PL
Chesi
M
Shou
Y
Kuehl
WM
Insertion of excised IgH switch sequences causes overexpression of cyclin D1 in a myeloma tumor cell.
Mol Cell
3
1999
119
127
Klein
U
Goossens
T
Fischer
M
Kanzler
H
Braeuninger
A
Rejewsky
K
Kuppers
R
Somatic hypermutation in normal and transformed B cells.
Immunol Rev
162
1998
261
128
Rabbitts
TH
Forster
A
Hamlyn
P
Baer
R
Effect of somatic mutation within translocated c-myc genes in Burkitt's lymphoma.
Nature
309
1984
592
129
Migliazza
A
Martinotti
S
Chen
W
Fusco
C
Ye
BH
Knowles
DM
Offit
K
Chaganti
RS
Dalla-Favera
R
Frequent somatic hypermutation of the 5′ noncoding region of the BCL6 gene in B-cell lymphoma.
Proc Natl Acad Sci USA
92
1995
12520
130
Shen
HM
Peters
A
Baron
B
Zhu
X
Storb
U
Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes.
Science
280
1998
1750
131
Pasqualucci
L
Migliazza
A
Fracchiolla
N
William
C
Neri
A
Baldini
L
Chaganti
RS
Klein
U
Kuppers
R
Rajewsky
K
Dalla-Favera
R
BCL-6 mutations in normal germinal center B cells: Evidence of somatic hypermutation acting outside Ig loci.
Proc Natl Acad Sci USA
95
1998
11816
132
Peng
H-Z
Du
M-Q
Koulis
A
Aiello
A
Dogan
A
Pan
L-X
Isaacson
PG
Nonimmunoglobulin gene hypermutation in germinal center B cells.
Blood
7
1999
2167
133
Gatti
RA
Ataxia-telangiectasia
The Metabolic and Molecular Bases for Inherited Disease
ed 8
Scrivner
CR
Beaudet
AL
Sly
WS
Valle
D
1998
McGraw-Hill
New York, NY
134
Savitsky
K
Bar-Shira
A
Gilad
S
Rotman
G
Ziv
Y
Vanagaite
L
Tagle
DA
Smith
S
Uziel
T
Sfez
S
Ashenazi
M
Pecker
I
Frydman
M
Harnik
R
Patanjali
SR
Simmons
A
Clines
GA
Sartiel
A
Gatti
RA
Chessa
L
Sanal
O
Lavin
MF
Jaspers
NGJ
Taylor
AMR
Arlett
CF
Miki
T
Weissman
SM
Lovett
M
Collins
FS
Shiloh
Y
A single ataxia telangiectasia gene with a product similar to PI-3 kinase.
Science
268
1995
1749
135
Morrell
D
Cromartie
E
Swift
M
Mortality and cancer incidence in 263 patients with ataxia-telangiectasia.
J Natl Cancer Inst
77
1986
89
136
Taylor
AM
Metcalfe
JA
Thick
J
Mak
YF
Leukemia and lymphoma in ataxia telangiectasia.
Blood
87
1996
423
137
Vorechovsky
I
Luo
L
Dyer
MJ
Catovsky
D
Amlot
PL
Yaxley
JC
Foroni
L
Hammarstrom
L
Webster
AD
Yuille
MA
Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia.
Nat Genet
17
1997
96
138
Stoppa-Lyonnet
D
Soulier
J
Lauge
A
Dastot
H
Garand
R
Sigaux
F
Stern
MH
Inactivation of the ATM gene in T-cell prolymphocytic leukemias.
Blood
91
1998
3920
139
Stilgenbauer
S
Schaffner
C
Litterst
A
Liebisch
P
Gilad
S
Bar-Shira
A
James
MR
Lichter
P
Dohner
H
Biallelic mutations in the ATM gene in T-prolymphocytic leukemia.
Nat Med
3
1997
1155
140
Yuille
MA
Coignet
LJ
Abraham
SM
Yaqub
F
Luo
L
Matutes
E
Brito-Babapulle
V
Vorechovsky
I
Dyer
MJ
Catovsky
D
ATM is usually rearranged in T-cell prolymphocytic leukaemia.
Oncogene
16
1998
789
141
Stankovic
T
Weber
P
Stewart
G
Bedenham
T
Murray
J
Byrd
PJ
Moss
PA
Taylor
AM
Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia.
Lancet
353
1999
26
142
Bullrich
F
Rasio
D
Kitada
S
Starostik
P
Kipps
T
Keating
M
Albitar
M
Reed
JC
Croce
CM
ATM mutations in B-cell chronic lymphocytic leukemia.
Cancer Res
59
1999
24
143
Schaffner
C
Stilgenbauer
S
Rappold
GA
Dohner
H
Lichter
P
Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia.
Blood
94
1999
748
144
Kojis
TL
Gatti
RA
Sparkes
RS
The cytogenetics of ataxia telangiectasia.
Cancer Genet Cytogenet
56
1991
143
145
Ganesh
A
North
P
Thacker
J
Repair and misrepair of site-specific DNA double-strand breaks by human cell extracts.
Mutat Res
299
1993
251
146
Hsieh
CL
Arlett
CF
Lieber
MR
V(D)J recombination in ataxia telangiectasia, Bloom's syndrome, and a DNA ligase I-associated immunodeficiency disorder.
J Biol Chem
268
1993
20105
147
Khanna
KK
Keating
KE
Kozlov
S
Scott
S
Gatei
M
Hobson
K
Taya
Y
Gabrielli
B
Chan
D
Lees-Miller
SP
Lavin
MF
ATM associates with and phosphorylates p53: Mapping the region of interaction.
Nat Genet
20
1998
398
148
Matsuoka
S
Huang
M
Elledge
SJ
Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.
Science
282
1998
1893
149
Canman
CE
Lim
DS
Cimprich
KA
Taya
Y
Tamai
K
Sakaguchi
K
Appella
E
Kastan
MB
Siliciano
JD
Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.
Science
281
1998
1677
150
Banin
S
Moyal
L
Shieh
S
Taya
Y
Anderson
CW
Chessa
L
Smorodinsky
NI
Prives
C
Reiss
Y
Shiloh
Y
Ziv
Y
Enhanced phosphorylation of p53 by ATM in response to DNA damage.
Science
281
1998
1674
151
Weemaes
CM
Hustinx
TW
Scheres
JM
van Munster
PJ
Bakkeren
JA
Taalman
RD
A new chromosomal instability disorder: The Nijmegen breakage syndrome.
Acta Paediatr Scand
70
1981
557
152
Wegner
RD
Chrzanowska
KH
Spreling
K
Stumm
M
Ataxia-Telangiectasia variants (Nijmegen breakage syndrome)
Primary Immunodeficiency Diseases, a Molecular and Genetic Approach.
Ochs
HD
Smith
CIE
Puck
JM
1999
Oxford
Oxford, UK
153
Varon
R
Vissinga
C
Platzer
M
Cerosaletti
KM
Chrzanowska
KH
Saar
K
Beckmann
G
Seemanova
E
Cooper
PR
Nowak
NJ
Stumm
M
Weemaes
CM
Gatti
RA
Wilson
RK
Digweed
M
Rosenthal
A
Sperling
K
Concannon
P
Reis
A
Nibrin, a novel DNA double-strand break repair protein is mutated in Nijmegen breakage syndrome.
Cell
93
1998
467
154
Matsuura
S
Tauchi
H
Nakamura
A
Kondo
N
Sakamoto
S
Endo
S
Smeets
D
Solder
B
Belohradsky
BH
Der Kaloustian
VM
Oshimura
M
Isomura
M
Nakamura
Y
Komatsu
K
Positional cloning of the gene for Nijmegen breakage syndrome.
Nat Genet
19
1998
179
155
Carney
JP
Mase
RS
Olivares
H
Davis
EM
Le Beau
M
Yates
JRI
Hays
L
Morgan
WF
Petrini
JHJ
The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: Linkage of double-strand break repair to the cellular DNA damage response.
Cell
93
1998
477
156
Nelms
BE
Maser
RS
MacKay
JF
Lagally
MG
Petrini
JH
In situ visualization of DNA double-strand break repair in human fibroblasts.
Science
280
1998
590
157
Haber
JE
The many interfaces of Mre11.
Cell
95
1998
583
158
Paull
TT
Gellert
M
The 3′ to 5′ exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks.
Mol Cell
1
1998
969
159
Paull
TT
Gellert
M
Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex.
Genes Dev
13
1999
1276
160
Critchlow
SE
Jackson
SP
DNA end-joining: from yeast to man.
Trends Biochem Sci
23
1998
394
161
Ellis
NA
Groden
J
Ye
TZ
Straughen
J
Lennon
DJ
Ciocci
S
Proytcheva
M
German
J
The Bloom's syndrome gene product is homologous to RecQ helicases.
Cell
83
1995
655
162
German
J
Bloom's syndrome. XX. The first 100 cancers.
Cancer Genet Cytogenet
93
1997
100
163
Chaganti
RS
Schonberg
S
German
J
A manyfold increase in sister chromatid exchanges in Bloom's syndrome lymphocytes.
Proc Natl Acad Sci USA
71
1974
4508
164
Warren
ST
Schultz
RA
Chang
CC
Wade
MH
Trosko
JE
Elevated spontaneous mutation rate in Bloom syndrome fibroblasts.
Proc Natl Acad Sci USA
78
1981
3133
165
Langlois
RG
Bigbee
WL
Jensen
RH
German
J
Evidence for increased in vivo mutation and somatic recombination in Bloom's syndrome.
Proc Natl Acad Sci USA
86
1989
670
166
Sack
SZ
Liu
Y
German
J
Green
NS
Somatic hypermutation of immunoglobulin genes is independent of the Bloom's syndrome DNA helicase.
Clin Exp Immunol
112
1998
248
167
Donehower
LA
Harvey
M
Slagle
BL
McArthur
MJ
Montgomery
CA
Jr
Butel
JS
Bradley
A
Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.
Nature
356
1992
215
168
Donehower
LA
Harvey
M
Vogel
H
McArthur
MJ
Montgomery
CA
Jr
Park
SH
Thompson
T
Ford
RJ
Bradley
A
Effects of genetic background on tumorigenesis in p53-deficient mice.
Mol Carcinogen
14
1995
16
169
Bosma
MJ
Carroll
AM
The SCID mouse mutant: Definition, characterization, and potential uses.
Annu Rev Immunol
9
1991
323
170
Bogue
MA
Zhu
C
Aguilar-Cordova
E
Donehower
LA
Roth
DB
p53 is required for both radiation-induced differentiation and rescue of V(D)J rearrangement in scid mouse thymocytes.
Genes Dev
10
1996
553
171
Guidos
CJ
Williams
CJ
Grandal
I
Knowles
G
Huang
MTF
Danska
JS
V(D)J recombination activates a p53-dependent DNA damage checkpoint in scid lymphocyte precursors.
Genes Dev
10
1996
2038
172
Nacht
M
Strasser
A
Chan
YR
Harris
AW
Schlissel
M
Bronson
RT
Jacks
T
Mutations in the p53 and SCID genes cooperate in tumorigenesis.
Genes Dev
10
1996
2055
173
Vanasse
GJ
Halbrook
J
Thomas
S
Burgess
A
Hoekstra
M
Disteche
CM
Willerford
DM
Genetic pathway to recurrent chromosome translocations in murine lymphoma involves V(D)J recombinase.
J Clin Invest
103
1999
1669
174
Liao
MJ
Zhang
XX
Hill
R
Gao
J
Qumsiyeh
MB
Nichols
W
Van Dyke
T
No requirement for V(D)J recombination in p53-deficient thymic lymphoma.
Mol Cell Biol
18
1998
3495
175
Nacht
M
Jacks
T
V(D)J recombination is not required for the development of lymphoma in p53-deficient mice.
Cell Growth Differ
9
1998
131
176
Kastan
MB
Zhan
Q
El-Deiry
W
Carrier
F
Jacks
T
Walsh
W
Plunkett
B
Vogelstein
B
Fornace
AJ
Jr
A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectaia.
Cell
71
1992
587
177
Clarke
AR
Purdie
CA
Harrison
DJ
Morris
RG
Bird
CC
Hooper
ML
Wyllie
AH
Thymocyte apoptosis induced by p53-dependent and independent pathways.
Nature
362
1993
849
178
Lowe
S
Schmitt
EM
Smith
SW
Osborne
BA
Jacks
T
p53 is required for radiation-induced apoptosis in mouse thymocytes.
Nature
362
1993
847
179
Danska
JS
Guidos
CJ
Essential and perilous: V(D)J recombination and DNA damage checkpoints in lymphocyte precursors.
Semin Immunol
9
1997
199
180
Diamond
RA
Ward
SB
Owada-Makabe
K
Wang
H
Rothenberg
EV
Different developmental arrest points in Rag-2−/− and SCID thymocytes on two genetic backgrounds.
J Immunol
158
1997
4052
181
Gutierrez
MI
Bhatia
K
Cherney
B
Capello
D
Gaidano
G
Magrath
I
Intraclonal molecular heterogeneity suggests a hierarchy of pathogenetic events in Burkitt's lymphoma.
Ann Oncol
8
1997
987
182
Hollstein
M
Sidransky
D
Vogelstein
B
Harris
CC
p53 mutations in human cancers.
Science
253
1991
49
183
Ichikawa
A
Kinoshita
T
Watanabe
T
Kato
H
Nagai
H
Tsushita
K
Saito
H
Hotta
T
Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma.
N Engl J Med
337
1997
529
184
Li
F
Fraumeni
JF
Jr
Mulvihill
JJ
Blattner
WA
Dreyfus
MG
Tucker
MA
Miller
RW
A cancer family syndrome in twenty-four kindreds.
Cancer Res
48
1988
5358
185
Malkin
D
Li
FP
Strong
LC
Fraumeni
JF
Jr
Kim
DH
Kassel
J
Gryka
MA
Bischoff
FZ
Tainsky
MA
Friend
SH
Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.
Science
250
1990
1233
186
Levine
AJ
p53, the cellular gatekeeper for growth and division.
Cell
88
1997
323
187
Barlow
C
Hirotsune
S
Paylor
R
Liyanage
M
Eckhaus
M
Collins
F
Shiloh
Y
Crawley
JN
Ried
T
Tagle
D
Wynshaw-Boris
A
Atm-deficient mice: A paradigm of ataxia telangiectasia.
Cell
86
1996
159
188
Liyanage
M
Coleman
A
du Manoir
S
Veldman
T
McCormack
S
Dickson
RB
Barlow
C
Wynshaw-Boris
A
Janz
S
Wienberg
J
Ferguson-Smith
MA
Schrock
E
Ried
T
Multicolour spectral karyotyping of mouse chromosomes.
Nat Genet
14
1996
312
189
Li
GC
Ouyang
H
Li
X
Nagasawa
H
Little
JB
Chen
DJ
Ling
CC
Fuks
Z
Cordon-Cardo
C
Ku70: A candidate tumor suppressor gene for murine T cell lymphoma.
Mol Cell
2
1998
1
190
Morrison
C
Smith
GCM
Stingl
L
Jackson
SP
Wagner
EF
Wang
Z-Q
Genetic interaction between PARP and DNA-PK in V(D)J recombination and tumorigenesis.
Nat Genet
17
1997
479
191
Baross-Francis
A
Andrew
SE
Penney
JE
Jirik
FR
Tumors of DNA mismatch repair-deficient hosts exhibit dramatic increases in genomic instability.
Proc Natl Acad Sci USA
95
1998
8739
192
de Wind
N
Dekker
M
Berns
A
Radman
M
te Riele
H
Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer.
Cell
82
1995
321
193
Reitmair
AH
Schmits
R
Ewel
A
Bapat
B
Redston
M
Mitri
A
Waterhouse
P
Mittrucker
HW
Wakeham
A
Liu
B
Thomason
A
Griesser
H
Gallinger
S
Ballhausen
WG
Fishel
R
Mak
TW
MSH2 deficient mice are viable and susceptible to lymphoid tumours.
Nat Genet
11
1995
64
194
Shi
YP
Mohapatra
G
Miller
J
Hanahan
D
Lander
E
Gold
P
Pinkel
D
Gray
J
FISH probes for mouse chromosome identification.
Genomics
45
1997
42
195
Han
JO
Steen
SB
Roth
DB
Intermolecular V(D)J recombination is prohibited specifically at the joining step.
Mol Cell
3
1999
331
196
Lin
WC
Desiderio
S
Cell cycle regulation of V(D)J recombination-activating protein RAG-2.
Proc Natl Acad Sci USA
91
1994
2733
197
Harris
NL
Jaffe
ES
Stein
H
Banks
PM
Chan
JK
Cleary
ML
Delsol
G
De Wolf-Peeters
C
Falini
B
Gatter
KC
A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group.
Blood
84
1994
1361
198
Mitelman
F
Mertens
F
Johansson
B
A breakpoint map of recurrent chromosomal rearrangements in human neoplasia.
Nat Genet
15
1997
417
(special number)

Author notes

Address reprint requests to Dennis M. Willerford, MD, Division of Hematology, University of Washington School of Medicine, Box 357710, Seattle, WA 98195; e-mail: dwiller@u.washington.edu.

Sign in via your Institution