Coding and noncoding: the CLL mix

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BlankBlood, 13 May 2010, Vol. 115, No. 19, pp. 3858-3859.

Coding and noncoding: the CLL mix

Deepa Sampath, and A. Calin

M. D. ANDERSON CANCER CENTER

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 [kappa]B (NF-[kappa] 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-[kappa]B signaling, an action that is likely to compromise CLL survival. The

NF-[kappa]B 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!

Footnotes

Conflict-of-interest disclosure: The authors declare no competing financial

interests.

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2002;99(24):15524–15529.[Abstract/Free Full Text]

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