Submitted May 7, 2007
Accepted April 20, 2008
Dysfunctional homologous recombination mediates genomic instability and progression in myeloma
Masood A Shammas, Robert J. Shmookler Reis, Hemanta Koley, Ramesh B. Batchu, Cheng Li, and Nikhil C Munshi*
Department of Medicine, VA Health Care System and Harvard Medical School, Boston, MA, United States
Department of Geriatrics and Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, United States
Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA, United States
* Corresponding author; email: nikhil_munshi{at}dfci.harvard.edu.
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. The molecular basis for the generation of this genetic diversity in cancer cells thus has important implication in understanding cancer progression. Here we report that homologous recombination (HR) activity is elevated in multiple myeloma (MM) cells and leads to increased rate of mutation and progressive accumulation of genetic variation over time. We demonstrate that the inhibition of HR activity in MM cells by siRNAs targeting recombinase leads to significant reduction in the acquisition of new genetic changes in the genome; and conversely, 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.
