An oncogenic tyrosine kinase inhibits DNA repair and DNA-damage-induced Bcl-xL 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 p56lck-F505Y mice do not develop tumors, whereas their CD45−/−p56lck-F505Y progeny develop T lymphomas. Increased but nononcogenic p56lck kinase activity in p56lck-F505Y mice DN thymocytes causes cell-cycle progression, survival, and Bcl-XL upregulation. Additional unique oncogenic signals occur in pretumorigenic CD45−/−p56lck-F505Y thymocytes in which p56lck kinase activity is 2- to 3-fold higher relative to p56lck-F505Y: inhibition of DNA repair, inhibition of DNA-damage-induced Bcl-XL deamidation, Bax conformational change and mitochondrial translocation, cytochrome c release, and the apoptotic caspase execution cascade. Inhibition of Bcl-XL deamidation may be a critical switch in oncogenic kinase-induced T cell transformation.