An oncogenic tyrosine kinase inhibits DNA repair and DNAdamage-induced Bcl-X-L deamidation in T cell transformation

A transgenic mouse model of T cell lymphoma was used to investigate the transforming events mediated by an oncogenic tyrosine kinase in pretumorigenic CD4(-)CD8(-) (DN) thymocytes. Parental CD45(-/-) and p56(Ick-F505Y) mice do not develop tumors, whereas their CD45(-/-)p56(Ick-F505Y) progeny develop T lymphomas. Increased but nononcogenic p56(Ick) kinase activity in p56(Ick-F505Y) mice DN thymocytes causes cell-cycle progression, survival, and Bcl-X-L upregulation. Additional unique oncogenic signals occur in pretumorigenic CD45(-/-)p56(Ick-F505Y) thymocytes in which p56(Ick) kinase activity is 2- to 3-fold higher relative to p56(Ick-F505Y): inhibition of DNA repair, inhibition of DNA-damage-induced Bcl-X-L deamidation, Bax conformational change and mitochondrial translocation, cytochrome c release, and the apoptotic caspase execution cascade. Inhibition of Bcl-X-L deamidation may be a critical switch in oncogenic kinase-induced T cell transformation.