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Blood, 5 March 2009, Vol. 113, No. 10, pp. 2290-2297. Prepublished online as a Blood First Edition Paper on December 2, 2008; DOI 10.1182/blood-2007-05-089193. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-05-089193v1 113/10/2290    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Shammas, M. A. Articles by Munshi, N. C. Search for Related Content PubMed PubMed Citation Articles by Shammas, M. A. Articles by Munshi, N. C. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Dysfunctional homologous recombination mediates genomic instability and progression in myeloma Masood A. Shammas1,2, Robert J. Shmookler Reis3, Hemanta Koley1, Ramesh B. Batchu1, Cheng Li2, and Nikhil C. Munshi1,2 1 Department of Medicine, VA Health Care System and Harvard Medical School Boston, MA; 2 Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA; and 3 Department of Geriatrics, and Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, and Central Arkansas Veterans Healthcare System, Little Rock A prominent feature of most if not all cancers is a striking genetic instability, leading to ongoing accrual of mutational changes, some of which underlie tumor progression, including acquisition of invasiveness, drug resistance, and metastasis. Thus, the molecular basis for the generation of this genetic diversity in cancer cells has important implications in understanding cancer progression. Here we report that homologous recombination (HR) activity is elevated in multiple myeloma (MM) cells and leads to an increased rate of mutation and progressive accumulation of genetic variation over time. We demonstrate that the inhibition of HR activity in MM cells by small inhibitory RNA (siRNAs) targeting recombinase leads to significant reduction in the acquisition of new genetic changes in the genome and, conversely, the induction of HR activity leads to significant elevation in the number of new mutations over time and development of drug resistance in MM cells. These data identify dysregulated HR activity as a key mediator of DNA instability and progression of MM, with potential as a therapeutic target. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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