Abstract 2406: Epigenetics of chromosomal breakage sites and translocations

Abstract

Abstract Chromosomal translocations are genetic hallmarks of most cancer cells. Translocations require the formation of DNA double-strand breaks (DSBs) at two or more genomic loci, followed by the illegitimate joining of broken chromosomal ends through DNA repair. There is increasing evidence that translocations occur at non-random sites in the genome, suggesting that certain regions of the genome are more susceptible to DNA breakage than others. We hypothesize that altered chromatin structure predisposes genomic sites to DNA breakage and translocations. To identify chromatin features that facilitate translocations, we have mapped histone modifications and DNase I hypersensitive sites (DHSs) at translocation-prone regions in anaplastic large cell lymphoma (ALCL) precursor cells. We find enrichment of active histone marks and a decrease in repressive marks near frequent translocation breakpoints. In a complementary approach using genome-wide histone modification mapping we have identified altered chromatin features at common leukemia and lymphoma breakpoints in CD34+ hematopoietic stem cells. In order to directly test the role of chromatin features in DNA breakage susceptibility, we have developed a protein-DNA tethering system that allows us to create local chromatin domains at pre-defined sites in the genome containing inducible DSB sites in vivo. By measuring the amount of DSBs using ligation-mediated PCR, we find that histone modifying enzymes that create active chromatin marks generally increase breakage susceptibility; however, repressive marks do not necessarily decrease breakage susceptibility. This suggests the involvement of other factors in breakage susceptibility. Taken together, these experiments provide first insights into the role of chromatin structure in the formation of nonrandom chromosomal breaks and the mechanisms that lead to clinically relevant translocations. Citation Format: Bharat Burman, Zhuzhu Zhang, Rebecca Burgess, Vassilis Roukos, Jason Lieb, Tom Misteli. Epigenetics of chromosomal breakage sites and translocations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2406. doi:10.1158/1538-7445.AM2014-2406