Chronic lymphocytic leukemia (CLL) is the most common human leukemia and is characterized by predominantly nondividing malignant B cells overexpressing the antiapoptotic B cell lymphoma 2 (Bcl2) protein. miR-15a and miR-16-1 are deleted or down-regulated in the majority of CLLs. Here, we demonstrate that miR-15a and miR-16-1 expression is inversely correlated to Bcl2 expression in CLL and that both microRNAs negatively regulate Bcl2 at a posttranscriptional level. BCL2 repression by these microRNAs induces apoptopsis in a leukemic cell line model. Therefore, miR-15 and miR-16 are natural antisense Bcl2 interactors that could be used for therapy of Bcl2-overexpressing tumors.

Progress in understanding the biology of multiple myeloma (MM), a plasma cell malignancy, has been slow. The discovery of microRNAs (miRNAs), a class of small noncoding RNAs targeting multiple mRNAs, has revealed a new level of gene expression regulation. To determine whether miRNAs play a role in the malignant transformation of plasma cells (PCs), we have used both miRNA microarrays and quantitative real time PCR to profile miRNA expression in MM-derived cell lines (n ‫؍‬ 49) and CD138؉ bone marrow PCs from subjects with MM (n ‫؍‬ 16), monoclonal gammopathy of undetermined significance (MGUS) (n ‫؍‬ 6), and normal donors (n ‫؍‬ 6). We identified overexpression of miR-21, miR-106bϳ25 cluster, miR181a and b in MM and MGUS samples with respect to healthy PCs. Selective up-regulation of miR-32 and miR-17ϳ92 cluster was identified in MM subjects and cell lines but not in MGUS subjects or healthy PCs. Furthermore, two miRNAs, miR-19a and 19b, that are part of the miR-17ϳ92 cluster, were shown to down regulate expression of SOCS-1, a gene frequently silenced in MM that plays a critical role as inhibitor of IL-6 growth signaling. We also identified p300-CBP-associated factor , a gene involved in p53 regulation, as a bona fide target of the miR106bϳ25 cluster, miR-181a and b, and miR-32. Xenograft studies using human MM cell lines treated with miR-19a and b, and miR-181a and b antagonists resulted in significant suppression of tumor growth in nude mice. In summary, we have described a MM miRNA signature, which includes miRNAs that modulate the expression of proteins critical to myeloma pathogenesis.PCAF ͉ SOCS-1 ͉ tumor suppressor gene ͉ MGUS ͉ plasma cells

MicroRNAs (miRNAs) are short noncoding RNAs regulating gene expression that play roles in human diseases, including cancer. Each miRNA is predicted to regulate hundreds of transcripts, but only few have experimental validation. In chronic lymphocytic leukemia (CLL), the most common adult human leukemia, miR-15a and miR-16-1 are lost or down-regulated in the majority of cases. After our previous work indicating a tumor suppressor function of miR-15a/16-1 by targeting the BCL2 oncogene, here, we produced a high-throughput profiling of genes modulated by miR-15a/16-1 in a leukemic cell line model (MEG-01) and in primary CLL samples. By combining experimental and bioinformatics data, we identified a miR-15a/16-1-gene signature in leukemic cells. Among the components of the miR-15a/ 16-1 signature, we observed a statistically significant enrichment in AU-rich elements (AREs). By examining the Gene Ontology (GO) database, a significant enrichment in cancer genes (such as MCL1, BCL2, ETS1, or JUN) that directly or indirectly affect apoptosis and cell cycle was found. (5), PicTar (6), and Diana microT (7) have been developed to identify miRNA targets, but only few of these predictions have been experimentally validated, supporting the rationale for a combination of bioinformatics and biological strategies to this aim. Two independent studies predicted that 20-30% of human genes could be controlled by miRNAs (8, 9). Deviations from normal miRNA expression patterns play roles in human diseases, including cancer (for reviews see refs. 10-15).The miR-15a/16-1 cluster resides at chromosome 13q14.3, a genomic region frequently deleted in B cell chronic lymphocytic leukemias (CLLs), and the two members of the cluster are cotranscribed and down-regulated in the majority of CLL patients (16). CLL is a disease with a frequent association in families (10-20% of patients have at least one first-degree relative with CLL) (17). Previously, we identified germ-line or somatic mutations in several miRNAs (including miR-16-1) in Ϸ15% of CLL patients, with the majority of the patients having a known personal or family history of CLL or other hematopoietic and solid tumors (18). These findings, together with the identification of an abnormal miR-15a/ 16-1 locus in the NZB strain of mice that naturally develop CLL (19), suggest that this cluster might play also a role in familial CLL.Among the targets of miR-15a and miR-16, we identified the antiapoptotic protein Bcl2, which is overexpressed in the malignant, mostly nondividing B cells of CLL (20), and in many solid and hematologic malignancies (21). Restoration of miR-15-a/16-1 induces apoptosis in MEG-01, a cell line derived from acute megakaryocytic leukemia (22). These data support a role for miR-15a and miR-16-1 as tumor-suppressor genes (TSGs) in CLLs and perhaps in other malignancies in which these genes are lost or down-regulated.Here, to investigate the mechanism of action of miR-15a and miR-16-1 as tumor suppressors in leukemias, we analyzed the effects of miR-15a and miR-16-1 on...

MicroRNAs (miRNAs) encoded by the miR-15/16 cluster are known to act as tumor suppressors. Expression of these miRNAs inhibits cell proliferation, promotes apoptosis of cancer cells, and suppresses tumorigenicity both in vitro and in vivo. miR-15a and miR-16-1 function by targeting multiple oncogenes, including BCL2, MCL1, CCND1, and WNT3A. Down-regulation of these miRNAs has been reported in chronic lymphocytic lymphoma (CLL), pituitary adenomas, and prostate carcinoma. This review summarizes the discovery, functions, and clinical relevance of these miRNAs in cancer, particularly CLL.