Role of H2AX and ATM in Suppression of Thymic Lymphomas

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DESCRIPTION (provided by applicant): Immature T cell lymphomas account for a significant portion of human lymphoid malignancies and are a clinical problem as they are typically resistant to treatment. Many of these tumors harbor recurrent inter-chromosomal translocations and intra-chromosomal rearrangements (deletions) that activate proto-oncogenes, inactivate tumor suppressor genes, or create novel oncogenic fusion genes. Most oncogenic translocations of human immature T cell lymphomas likely arise through errors in the repair of specific DNA double strand breaks (DSBs) introduced at T cell receptor (TCR) loci during initiation of V(D)J recombination and/or more general DSBs at other genomic locations. In this context, mice deficient for the Ataxia Telangiectasia mutated (ATM) tumor suppressor protein, which can be inactivated in human immature T cell lymphomas, invariably develop thymic lymphoma with oncogenic TCR locus translocations. On the other hand, mice deficient or haplo-insufficient for histone H2AX and deficient for the p53 tumor suppressor rapidly and reproducibly succumb to immature T cell lymphomas with clonal translocations that, frequently, do not involve TCR loci and, instead, involve more general DSBs. Notably, H2AX is closely linked to ATM in both mice and man in a chromosomal region that in man is altered in a large number of cancers. In this application, we propose to elucidate mechanisms that lead to chromosomal translocations associated with T cell lymphomas. A major goal of this work will be to test our hypothesis that heterozygous or homozygous mutations of H2AX will function synergistically with loss of ATM to increase translocations and predisposition to tumors including thymic lymphomas. For this purpose, we will use sequential gone-targeting to generate cells and mice with combined H2AX and ATM mutations. Other experiments will test the hypothesis that ATM and H2AX prevent translocations resulting from aberrant V(D)J recombination by functioning to stabilize synaptic complexes of cleaved TCR chromosomal gone segments. Several novel approaches will be employed to test this notion, including the generation of mice which will be prone to frequent chromosomal translocations resulting from aberrant V(D)J recombination. Finally, we will also exploit thymic lymphoma-prone mouse models to test the role of TCR locus enhancer elements in the generation of oncogenic translocations. Frequent interaction with investigators in this program will greatly enhance the accomplishment of our goals as outlined. In the long term, our studies, and the mouse models that we will generate, should lead to a greater understanding of the molecular pathways which lead to thymic malignancies and which also are likely involved in the development of many other types of cancer.