Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia

Leukemia. 2015 Jan;29(1):86-95. doi: 10.1038/leu.2014.139. Epub 2014 Apr 15.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Base Sequence
  • Biomarkers, Tumor / genetics
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • DNA / genetics
  • DNA Copy Number Variations
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • MicroRNAs / genetics*
  • Molecular Sequence Data
  • Polymorphism, Single Nucleotide
  • Real-Time Polymerase Chain Reaction
  • Transcription, Genetic*

Substances

  • Biomarkers, Tumor
  • MIRN15 microRNA, human
  • MIRN16 microRNA, human
  • MicroRNAs
  • DNA