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Blood, 25 June 2009, Vol. 113, No. 26, pp. 6669-6680. Prepublished online as a Blood First Edition Paper on April 28, 2009; DOI 10.1182/blood-2009-01-198408. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2009-01-198408v1 113/26/6669    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Roccaro, A. M. Articles by Ghobrial, I. M. Search for Related Content PubMed PubMed Citation Articles by Roccaro, A. M. Articles by Ghobrial, I. M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 7, 2009 Accepted April 4, 2009 microRNAs 15a and 16 regulate tumor proliferation in multiple myeloma Aldo M. Roccaro, Antonio Sacco, Brian Thompson, Xavier Leleu, Abdel Kareem Azab, Feda Azab, Judith Runnels, Xiaoying Jia, Hai T. Ngo, Molly R. Melhem, Charles P. Lin, Domenico Ribatti, Barrett J. Rollins, Thomas E. Witzig, Kenneth C. Anderson, and Irene M. Ghobrial* Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy Department of Hematology, Mayo Clinic, Rochester, MN, United States * Corresponding author; email: irene_ghobrial{at}dfci.harvard.edu. Detailed genomic studies have shown that cytogenetic abnormalities contribute to multiple myeloma (MM) pathogenesis and disease progression. Nevertheless, little is known about the characteristics of MM at the epigenetic level, and specifically how microRNAs regulate MM progression in the context of the bone marrow milieu. Therefore, we performed microRNA expression profiling of bone marrow derived CD138+ MM cells versus their normal cellular counterparts, and validated data by qRT-PCR. We identified a MM-specific microRNA signature characterized by down-expression of microRNA-15a/-16 and over-expression of microRNA-222/-221/-382/-181a/-181b (P<0.01). We investigated the functional role of microRNA-15a and -16 and showed that they regulate proliferation and growth of MM cells in vitro and in vivo by inhibiting AKT serine/threonine-protein-kinase (AKT3), ribosomal-protein-S6, MAP-kinases, and NF-B-activator MAP3KIP3. Moreover, miRNA-15a and -16 exerted their anti-MM activity even in the context of the bone marrow milieu in vitro and in vivo. These data indicate that microRNAs play a pivotal role in the biology of MM; and represent important targets for novel therapies in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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