microRNAome Expression in Chronic Lymphocytic Leukemia: Comparison with Normal B-cell Subsets and Correlations with Prognostic and Clinical Parameters

Abstract

Purpose: Despite its indolent nature, chronic lymphocytic leukemia (CLL) remains an incurable disease. To establish the potential pathogenic role of miRNAs, the identification of deregulated miRNAs in CLL is crucial.Experimental Design: We analyzed the expression of 723 mature miRNAs in 217 early-stage CLL cases and in various different normal B-cell subpopulations from tonsils and peripheral blood.Results: Our analyses indicated that CLL cells exhibited a miRNA expression pattern that was most similar to the subsets of antigen-experienced and marginal zone-like B cells. These normal subpopulations were used as reference to identify differentially expressed miRNAs in comparison with CLL. Differences related to the expression of 25 miRNAs were found to be independent from IGHV mutation status or cytogenetic aberrations. These differences, confirmed in an independent validation set, led to a novel comprehensive description of miRNAs potentially involved in CLL. We also identified miRNAs whose expression was distinctive of cases with mutated versus unmutated IGHV genes or cases with 13q, 11q, and 17p deletions and trisomy 12. Finally, analysis of clinical data in relation to miRNA expression revealed that miR26a, miR532-3p, miR146-5p, and miR29cà were strongly associated with progressionfree survival. Conclusion:This study provides novel information on miRNAs expressed by CLL and normal B-cell subtypes, with implication on the cell of origin of CLL. In addition, our findings indicate a number of deregulated miRNAs in CLL, which may play a pathogenic role and promote disease progression. Collectively, this information can be used for developing miRNA-based therapeutic strategies in CLL. Clin Cancer Res; 20(15); 4141-53. Ó2014 AACR.

Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia

“…17,19,50,51 Increased miR-34a levels have been noted in several CLL studies. 26,29,52,53 Inhibition of miR-34a by antisense RNA has been shown to sensitize lymphoma cells to apoptosis. 54 We found that levels of miR-34a were 87-fold higher in circulating CLL cells in comparison to normal circulating B-cells; and miR-34a was significantly higher in CLL cells in the lymph node than that in the peripheral blood.…”

“…26,27 miR-34a and miR-146b were both previously reported to target SMAD4; 39-42 and miR-34 was reported to target HDAC1 43,44 in solid tumor cell lines resulting in inhibition of both mRNA and protein expression. In order to confirm inhibition of mRNA transcripts and protein expression regulated by miR-34a and miR146b in B-cell leukemia cell lines, premiR oligonucleotides were transfected into SP53 and MEC1 cells.…”

“…24,25 Aberrant miRNA expression profiles in CLL PB have been previously reported to have prognostic significance. 26,27 Calin et al identified a panel of thirteen out of 190 miRNAs that could discriminate between aggressive CLL (ZAP-70 high expression and unmutated IGHV) versus indolent CLL (ZAP-70 low expression and mutated IGHV). 27 High levels of miR-21 are reportedly associated with a poor prognosis in CLL patients with a 17p deletion; while low levels of miR-181b reportedly identify patients who may benefit from early therapeutic intervention.…”

Expression of circulating miRNAs associated with lymphocyte differentiation and activation in CLL—another piece in the puzzle

“…The exact role of miR-15/16 in CLL was reviewed in detail by Pekarsky and Croce [17]. Many studies addressed miRNA expression in lymphocytes of CLL patients and tested its correlation with clinical and prognostic parameters [38–41]. New possibilities have opened with the discovery of circulating miRNAs.…”

Mir-34: A New Weapon Against Cancer?

“…2,3,4 MiRNAs are dysregulated in almost all solid and hematological malignancies, and specific signatures allow the characterization of poorly differentiated tumors 5 as well as harbor relevant clinical implications. 6,7,8,9 MiRNAs, which are upregulated in cancer cells and contribute to carcinogenesis by inhibiting tumor suppressor genes, are considered oncogenic miRNAs (OncomiRs), 10 while downregulated miRNAs, that normally prevent cancer development by inhibiting the expression of proto-oncogenes, are known as tumor suppressor miRNAs. 11 Silencing Oncomirs with miRNA inhibitors or replacing tumor suppressor miRNAs with synthetic miRNA mimics is demonstrating a valuable experimental strategy for the treatment of solid and hematological malignancies.…”