Development of T-leukaemias in CD45 tyrosine phosphatase-deficient mutant lck mice

The CD45 tyrosine phosphatase lowers T-cell antigen receptor signalling thr esholds by its positive actions on p56(lck) tyrosine kinase function. We no w show that mice expressing active lck(F505) at non-oncogenic levels develo p aggressive thymic lymphomas on a CD45(-/-) background. CD45 suppresses th e tumorigenic potential of the kinase by dephosphorylation of the Tyr394 au tophosphorylation site. In CD45-/- thymocytes the kinase is switched to a h yperactive oncogenic state, resulting in increased resistance to apoptosis, Transformation occurs in early CD4(-)CD8(-) thymocytes during the process of TCR-beta chain rearrangement by a recombinase-independent mechanism. Our findings represent the first example in which a tyrosine phosphatase in si tu prevents the oncogenic actions of a Src family tyrosine kinase.