Flavia Pichiorri1, Sung Suk Suh2,3, Marco Ladetto4, Michael Kuehl5, Tiziana Palumbo2,3, Daniela Drandi4, Cristian Taccioli2,3, Nicola Zanesi2,3, Hansjüerg Alder2,3, John P. Hagan2,3, Reinhold Munker6, Stefano Volinia2,3, Mario Boccadoro4, Ramiro Garzon7, Antonio Palumbo4, Rami I. Aqeilan2,8,3, Carlo M. Croce2,3
1Department of Molecular Virology, Ohio State University, Columbus, OH 43210, USA.
2Departments of *Molecular Virology, Immunology, and Human Genetics, and
3The Ohio State University
4Division of Hematology, University of Torino, 10126 Torino, Italy;
5Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889-5105; and
6Division of Hematology/Oncology, Louisian State University Health Sciences Center, Louisiana State University, Shreveport, LA 71130
7Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;
8[Hebrew university of Jerusalem]
Tóm tắt
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 ofmiR-21,miR-106b∼25cluster,miR-181aandbin MM and MGUS samples with respect to healthy PCs. Selective up-regulation ofmiR-32andmiR-17∼92cluster was identified in MM subjects and cell lines but not in MGUS subjects or healthy PCs. Furthermore, two miRNAs,miR-19aand19b, that are part of themiR-17∼92cluster, 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 ofthe miR106b∼25cluster,miR-181aandb, andmiR-32. Xenograft studies using human MM cell lines treated withmiR-19aandb, andmiR-181aandbantagonists 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.
