Mechanisms promoting translocations and mature B cell lymphomas

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DESCRIPTION (provided by applicant): Most human mature B cell lymphomas appear derived from germinal center (GC) or post-GC B cells and often harbor clonal translocations involving immunoglobulin (Ig) and oncogenes. The GC is a special microenvironment formed by mature B cells in response to antigens, where B cells proliferate vigorously and Ig genes undergo two DNA alteration events, somatic hypermutation (SHM) and class switch recombination (CSR). While it has been proposed that DNA double strand breaks (DSBs) during SHM or CSR are the primary sources of chromosomal translocations in GC-derived B cell lymphomas, this point has never been directly addressed due to the lack of proper mouse models. There are a few nicely characterized mouse models for GC-derived B cell lymphomas. However, most of these models are based on constitutive expression of oncogenes via lymphocyte-specific regulatory regions, an approach that fails to generate tumors with clonal translocations. We present a novel and unique model that we established based on the conditional deletion of a DSB repair factor specifically in GC B cells. We propose to employ our unique mouse model and new techniques to elucidate the mechanisms promoting translocation and lymphomagenesis in mature B cells by: 1) determining whether increased frequency of DSBs in GC B cells promote translocations that predispose to mature B cell lymphomas; 2) testing whether spatial proximity of target loci influence the translocation frequency in GC B cells. The completion of our proposal will lead to better understanding of the specific processes during which translocations arise and the mechanisms that regulate the propensity of specific loci to form translocations. Our studies may also identify novel candidate oncogenes or tumor suppressor genes that are targeted by clonal translocations and could potentially serve as therapeutic targets. Finally, the comprehensive analysis of primary GC B cell translocations will provide major new insight into the molecular mechanism of translocation and have broader impact in the field of DNA damage and repair. Relevance to Public Health: It is widely accepted that chromosomal translocation can promote cancer development by disrupting tumor suppressors, activating oncogenes, or generating aberrant fusion proteins. Furthermore, cancer type-specific chromosomal translocations are frequently identified in leukemia and lymphomas, and increasingly found in solid tumors such as TMPRSS2-ETS translocation in prostate cancer and ALK translocations in lung cancer. In this context, our proposed studies to investigate targeting mechanisms for chromosomal translocations will have broader impacts. Elucidation of such mechanisms will shed light on the etiology, diagnosis and treatment of cancer. PUBLIC HEALTH RELEVANCE: It is widely accepted that chromosomal translocation can promote cancer development by disrupting tumor suppressors, activating oncogenes, or generating aberrant fusion proteins. Furthermore, cancer type-specific chromosomal translocations are frequently identified in leukemia and lymphomas, and increasingly found in solid tumors such as TMPRSS2-ETS translocation in prostate cancer and ALK translocations in lung cancer. In this context, our proposed studies to investigate targeting mechanisms for chromosomal translocations will have broader impacts. Elucidation of such mechanisms will shed light on the etiology, diagnosis and treatment of cancer.