Abstract
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 lck-F505Y mice do not develop tumors, whereas their CD45 −/−p56 lck-F505Y progeny develop T lymphomas. Increased but nononcogenic p56 lck kinase activity in p56 lck-F505Y mice DN thymocytes causes cell-cycle progression, survival, and Bcl-X L upregulation. Additional unique oncogenic signals occur in pretumorigenic CD45 −/−p56 lck-F505Y thymocytes in which p56 lck kinase activity is 2- to 3-fold higher relative to p56 lck-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.
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