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Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia
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Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia
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Journal Article
Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia
2015
Overview
Deregulation of the miR-15a/16-1 cluster has a key role in the pathogenesis of chronic lymphocytic leukemia (CLL), a clinically heterogeneous disease with indolent and aggressive forms. The
miR-15a/16-1
locus is located at 13q14, the most frequently deleted region in CLL. Starting from functional investigations of a rare SNP upstream the miR cluster, we identified a novel allele-specific mechanism that exploits a cryptic activator region to recruit the RNA polymerase III for miR-15a/16-1 transcription. This regulation of the
miR-15a/16-
locus is independent of the
DLEU2
host gene, which is often transcribed monoallellically by RPII. We found that normally one allele of
miR-15a/16-1
is transcribed by RNAPII, the other one by RNAPIII. In our subset of CLL patients harboring 13q14 deletions, exclusive RNA polymerase III (RPIII)-driven transcription of the miR-15a/16-1 was the consequence of loss of the RPII-regulated allele and correlated with high expression of the poor prognostic marker ZAP70 (
P
=0.019). Thus, our findings point to a novel biological process, characterized by double allele-specific transcriptional regulation of the miR-15a/16-1 locus by alternative mechanisms. Differential usage of these mechanisms may distinguish at onset aggressive from indolent forms of CLL. This provides a basis for the clinical heterogeneity of the CLL patients carrying 13q14 deletions.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/31
/ 13/44
/ 13/89
/ 38/109
/ 38/15
/ 38/77
/ 38/90
/ 45/22
/ Alleles
/ Biomarkers, Tumor - genetics
/ Cancer
/ Chromatin Immunoprecipitation
/ Chronic lymphocytic leukemia
/ Humans
/ Leukemia, Lymphocytic, Chronic, B-Cell - genetics
/ Medicine
/ MicroRNA
/ Oncology
/ Original
/ Polymorphism, Single Nucleotide
