In this application, we propose to elucidate the molecular function of ATM in suppression of oncogenic translocations in developing lymphocytes and generate novel mouse models for human lymphoid malignancies. Lymphoid malignancies are characterized by recurrent translocations arise from errors incurred during the repair of developmental double strand breaks in lymphocytes. Molecular characterizations of recurrent translocations in lymphoid malignancies have led to the discovery of key oncogenes (e.g. C-MYC) and the development of targeted therapeutic approaches (e.g. Gleevec targeting BCR-ABL1). Here we will use ATM-deficient and conditional deficient mice as the model system to elucidate the mechanisms that underlie recurrent translocations in both B and T cells, including the how repair factor availability, developmental stage and enhancer elements affect translocation pattern and tumor spectrum. ATM kinase is a master regulator of DNA damage responses and is essential for efficient and precise repair of programmed double strand breaks generated at the antigen receptor loci during lymphocyte development. As a result, inactivation mutations of ATM cause Ataxia-Telangiectasia (A-T), a neurological disorder that is often associated with immunodeficiency. ATM deficiency also predisposes patients to both B and T cell malignancies with recurrent translocations involving antigen receptor loci. Somatic inactivation and deletion of ATM are often reported in sporadic B and T malignancies and is often associated with frequent cytogenetic alterations and aggressive phenotypes. ATM-deficient mice recapitulate the immunodeficiency and prone T-cell lymphoma phenotype of human patients. Moreover the recurrent clonal translocations in ATM- deficient mouse thymic lymphomas share molecular origins with those from human patients. However the precise mechanisms that generate such translocations or the mechanisms underlying their oncogenicity are not yet fully understood. On the hand, the aggressive T cell lymphoma and early lethality of ATM-deficient mice render it difficult to study the role of ATM in the etiology of the more prevalent B cell lymphomas. Therefore here we propose to 1) elucidate the molecular mechanism of the recurrent TCRalpha/delta locus related translocations in ATM-deficient mouse thymic lymphomas; 2) define and functionally validate the oncogenic targets for the recurrent translocations in ATM-deficient thymic lymphomas and the related immature T cell leukemias in human patients; and 3) determine the role of ATM in suppressing oncogenic translocations in developing B cells by generating and characterizing B cell specific conditional ATM-deficient lymphoma models. Together the results from this study will address the molecular mechanism of oncogenic translocations in developing lymphocytes and the functions of ATM in the etiology of lymphoid malignancies. Given the similarity between ATM-deficient mice thymic lymphomas and human immature T cell malignancies documented by us and others, our molecular analyses of ATM-deficient mouse lymphomas and their human counterparts will also lead to the discovery of oncogenic pathways that are important in human lymphoid malignancies.
Our proposed study addresses the molecular mechanism by which ATM suppresses oncogenic translocations in developing lymphocytes, identifies novel oncogenic targets for immature T cell lymphomas and generates novel mouse models to study the role of ATM in oncogenic transformation of developing B cells.
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