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Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

Abstract

Inactivating Tp53 mutations are frequent genetic lesions in human tumors that harbor genomic instability, including B lineage lymphomas with IG translocations. Antigen receptor genes are assembled and modified in developing lymphocytes by RAG/AID-initiated genomic rearrangements that involve the induction of DNA double strand breaks (DSBs). Although TP53 inhibits the persistence of DSBs and induces apoptosis to protect cells from genomic instability and transformation, the development of spontaneous tumors harboring clonal translocations has not been reported in mice that only lack wild-type Tp53 protein or express Tp53 mutants. Tp53-deficient (Tp53−/−) mice succumb to T lineage lymphomas lacking clonal translocations but develop B lymphoid tumors containing immunoglobulin (Ig) translocations upon combined inactivation of DSB repair factors, RAG mutation or AID overexpression; mice expressing apoptosis-defective Tp53 mutants develop B cell lymphomas that have not been characterized for potential genomic instability. As somatic rather than germline inactivating mutations of TP53 are typically associated with human cancers and Tp53 deletion has cellular context dependent effects upon lymphocyte transformation, we generated mice with conditional Tp53 deletion in lineage-committed B lymphocytes to avoid complications associated with defective Tp53 responses during embryogenesis and/or in multi-lineage potential cells and, thereby, directly evaluate the potential physiological role of Tp53 in suppressing translocations in differentiated cells. These mb1-cre:Tp53flox/flox mice succumbed to lymphoid tumors containing Ig gene rearrangements and immunophenotypes characteristic of B cells from various developmental stages. Most mb1-cre:Tp53flox/flox tumors harbored clonal translocations, including Igh/c-myc or other oncogenic translocations generated by the aberrant repair of RAG/AID-generated DSBs. Our data indicate that Tp53 serves critical functions in B lineage lymphocytes to prevent transformation caused by translocations in cell populations experiencing physiological levels of RAG/AID-initiated DSB intermediates, and provide evidence that the somatic TP53 mutations found in diffuse large B-cell lymphoma and Burkitt's lymphoma may contribute to the development of these human malignancies.

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Acknowledgements

This work was supported by the Training Program Rheumatic Disease of the University of Pennsylvania (5T32-AR007442-23 to MAWR), the Training Grant TG GM-07229 of the University of Pennsylvania (AD), the Cancer Research Institute Pre-doctoral Emphasis Pathway in Tumor Immunology Training Grant awarded to the University of Pennsylvania (BY); the Department of Pathology and Laboratory Medicine and the Center for Childhood Cancer Research of the Children's Hospital of Philadelphia Research Institute, the Abramson Family Cancer Research Institute of the University of Pennsylvania School of Medicine, a grant from the Pennsylvania Department of Health, a Leukemia and Lymphoma Society Scholar Award (CHB), and the National Institutes of Health Grant R01 CA125195 (CHB).

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Correspondence to C H Bassing.

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Rowh, M., DeMicco, A., Horowitz, J. et al. Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations. Oncogene 30, 4757–4764 (2011). https://doi.org/10.1038/onc.2011.191

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