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Visone R.,Ohio State University | Veronese A.,Ohio State University | Rassenti L.Z.,University of California at San Diego | Rassenti L.Z.,Chronic Lymphocytic Leukemia Research Consortium | And 9 more authors.
Blood | Year: 2011

MicroRNAs play a crucial role in chronic lymphocytic leukemia. We investigated whether microRNAs can discriminate patients with a progressive disease from patients with a stable disease. We analyzed microRNA expression on leukemic cells isolated from 358 sequential samples of 114 patients with either stable or progressive disease. We found that during the course of the disease the expression values of miR-181b, the most dysregulated microRNA, decreased in samples of patients with a progressive (P < .001, training and validation sets) but not in samples of patients with a stable disease (P = .3, training set; P = .2, validation set) over time. A drop of ≥ 50% between sequential samples and/or a miR-181b value ≤ 0.005 at the starting time point were significant to differentiate progressive from stable disease (P = .004, training set; P < .001, validation set). These parameters were associated with high risk of requiring treatment (risk ratio, 5.8; 95% confidence interval, 2.5-14.9). We also observed that miR-181b targets Mcl-1 protein and that the decrease of its expression inversely correlated with increased protein levels of MCL1 and BCL2 target genes. We conclude that parameters defined on the basis of the miR-181b expression values specify disease progression in chronic lymphocytic leukemia and are associated with clinical outcome. © 2011 by The American Society of Hematology.

Veronese A.,University of Chieti Pescara | Pepe F.,University of Chieti Pescara | Chiacchia J.,University of Chieti Pescara | Pagotto S.,University of Chieti Pescara | And 20 more authors.
Leukemia | Year: 2015

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. © 2015 Macmillan Publishers Limited.

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