The Src homology 2 domain of Bcr/Abl is required for efficient induction of chronic myeloid leukemia-like disease in mice but not for lymphoid leukemogenesis or activation of phosphatidylinositol 3-kinase

The effect of mutations in the Src homology 2 (SH2) domain of the BCR/ABL o ncogene on leukemogenesis was tested in a quantitative murine bone marrow t ransduction/transplantation assay that accurately models human Philadelphia -positive B-lymphoid leukemia and chronic myeloid leukemia (CML), The SH2 d omain was not required for induction of B-lymphoid leukemia in mice by BCR/ ABL, Under conditions where the p190 end p210 forms of BCR/ABL induce fatal CML-like myeloproliferative disease within 4 weeks, p210 SH2 mutants induc ed CML-like disease in some mice only after a significant delay, with other recipients succumbing to B-lymphoid leukemia instead. In contrast, p190 BC R/ABL SH2 point and deletion mutants rapidly induced CML-like disease, Thes e results provide the first direct evidence of significant differences in c ell signaling by the Bcr/Abl tyrosine kinase between these distinct leukemi as, Contrary to previous observations, high levels of phosphatidylinositol 3-kinase (PI 3-kinase) activity in primary malignant lymphoblasts end myelo id cells from recipients of marrow transduced with the BCR/ABL SH2 mutants were found, Hence, the decreased induction of CML-like disease by the p210 BCR/ABL SH2 mutants is not due to impaired activation of PI 3-kinase. (C) 2 001 by The American Society of Hematology.