Dysfunctional homologous recombination mediates genomic instability and progression in myeloma.
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.
Shammas
Masood A
MA
Department of Medicine, VA Health Care System and Harvard Medical School Boston, MA, USA.
Shmookler Reis
Robert J
RJ
Koley
Hemanta
H
Batchu
Ramesh B
RB
Li
Cheng
C
Munshi
Nikhil C
NC
D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D020869:Gene Expression Profiling; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D009101:Multiple Myeloma / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; C110901:X-ray repair cross complementing protein 3; C113187:XRCC2 protein, human; C495153:RAD51 protein, human; D051135:Rad51 Recombinase