Coding and noncoding: the CLL mix

In this issue of Blood, Palamarchuk and colleagues present interesting evidence that deletions in chromosome 13q result in a loss of expression of both the protein coding gene, dleu7 as well as the noncoding RNA cluster miR-15a-16-1. dleu7 and miR15a-16-1 may both have a role in the pathogenesis of CLL.

Chronic lymphocytic leukemia (CLL) is characterized by multiple and recurrent chromosomal abnormalities, of which deletions in chromosome 13q (del13q14) are the most frequent.¹  Monoallelic and biallelic deletions at the 13q14 locus occur in 55% and 16%, respectively, of all CLL, are of varying lengths, and at the very least involve a minimally deleted region of approximately 30 kb that was previously shown to lead to the loss of expression of the microRNAs, miR-15a-16-1.²  This cluster is located in an intron of the dleu2 gene within the 13q14 chromosomal locus and is down-regulated in the majority of CLLs.²  Loss of the cluster led to the spontaneous generation of CLL in mice,³  whereas ectopic expression of miR-15a-16 induced apoptosis in cell lines and suppressed tumorigenesis in xenograft models.⁴  The tumor suppressor function of miR-15a and miR-16-1 was linked to its ability to target the antiapoptotic survival proteins Bcl-2⁵  and Mcl-1.⁴  Bcl-2 and Mcl-1 function by sequestering proapoptotic members of the Bcl-2 family so as to prevent mitochondrial dysfunction and cell death. Consequently, loss of miR15a-16-1 is associated with enhanced survival.^3,4 

CLL is also characterized by the deregulated expression of the B-cell activating factor (BAFF), a potent regulator of normal B-cell development and function and a proliferation-inducing ligand (APRIL). Ligation of BAFF and APRIL to their cognate receptors, the B-cell maturation antigen (BCMA) and transmembrane activator or the calcium modulator and cyclophilin ligand-interactor (TACI) trigger the activation of nuclear factor of κB (NF-κB) that in turn activates signaling cascades that promote CLL survival.⁶ 

A high-resolution map of 13q14 deletions in CLL identified that the minimally deleted region contained the protein coding gene dleu7 in addition to dleu2-miR15a-16-1 noncoding gene.⁷  This study by Palamarchuk et al identified that the protein product of dleu7 directly bound to and inhibited the function of BCMA and TACI.⁸  Consequently, dleu7 functioned as a potent inhibitor of NF-κB signaling, an action that is likely to compromise CLL survival. The NF-κB suppressive action of dleu7 may in part explain its ability to function as a tumor suppressor in CLL. This paper highlights in a convincing manner the finding that cytogenetic abnormalities in CLL often result in the concomitant loss of proteins and noncoding RNAs such as dleu7 and miR15a-16-1 in del13q that function in parallel to suppress tumorigenesis. A very recent study takes into account the cellular consequences of losing dleu2 expression, the host gene on which miR-15a-16-1 reside: mice engineered to lose dleu2 in addition to miR15a-16-1 developed a more aggressive phenotype of CLL in contrast to mice that lost miR15a-16-1 alone,³  suggesting that the function of these tumor-suppressor genes is additive-suppressing tumorigenesis.

Other instances of genomic abnormalities that lead to the coordinate loss of protein coding and noncoding genes are exemplified by CLL subgroups that harbor deletions in chromosome 11q that result in the loss of expression of ATM as well as the microRNAs miR34b/c or deletions in chromosome 17p that lead to concurrent losses in p53 and miR-497.¹ 

In addition to genomic aberrations, the expression of dleu7 was also silenced due to aberrant DNA methylation. DNA methylation and histone modification-induced gene silencing of protein coding genes⁹  and microRNA genes¹⁰  occur in CLL and may serve to complement genomic losses in achieving a greater-than-expected gene silencing. Thus genetic and epigenetic aberrations control the expression of coding and noncoding genes that regulate CLL pathogenesis. The study by Palamarchuk and colleagues is important as it proves that the combination of abnormalities in both protein coding and noncoding genes is important for the pathogenesis of CLL and sometimes such players are located in the same short piece of genome that is found to be deleted in patient samples. And this is good news for both geneticists and hematologists hunting cancer genes!