Lymphoma is one of the most frequent cancers worldwide and the incidence is rising. The most commonly occurring human lymphomas represent mature B cells, of which many arise from GC B cells and are associated with characteristic chromosomal translocations that fuse immunoglobulin locus sequences with certain cellular oncogenes. Mouse models for human mature B cell lymphomas have been lacking. In work supported by this program project grant, we have now developed lymphoma models that share many characteristics with human B cell lymphomas, including the routine development of characteristic translocations. In particular, we have made a mouse model that reproducibly develops mature B cell lymphomas, termed CXP tumors, that arise when we conditionally inactivate a DNA double strand break (DSB) repair protein (XRCC4) in p53-deficient mature B cells. CXP B cell lymphomas routinely harbor a clonal translocation that fuses IgH switch (S) regions to exon 1 of c-Myc, as well as a second clonal translocation that fuses the IgX light chain locus into various chromosomal locations. Our ongoing studies wil focus on these models and related models being developed to address long-standing and fundamental questions regarding the mechanisms that generate and select for specific types of oncogenic translocations. In addition, our recent work has defined novel roles DNA DSB response factors, such as HistoneH2AX, in holding broken chromosomes together so that they can be repaired by NHEJ. Moreover, w have shown that defects in such factors can lead to broken chromosomes, translocations, and, in the appropriate backgrounds mature B cell lymphomas with clonal translocations. Our proposed studies will continue to elucidate the functions of this novel class of translocation and tumor suppressors and use conditional elimination of H2AX, as well as other approaches, to develop additional novel mature B cell lymphoma models. In the long term, our studies, and the mouse models that we will generate, should lead to a greater understanding of the molecular pathways that lead to B cell malignancies, as well as other types of cancer and facilitate development of novel treatments.