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

作者：Veronese A; Pepe F; Chiacchia J; Pagotto S; Lanuti P; Veschi S; Di Marco M; D'Argenio A; Innocenti I; Vannata B; Autore F; Marchisio M; Wernicke D; Verginelli F; Leone G; Rassenti L Z; Kipps T J; Mariani Costantini R; Laurenti L; Croce C M; Visone R^*

来源：Leukemia, 2015, 29(1): 86-95.

DOI：10.1038/leu.2014.139

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.

• 出版日期2015-1