ALTERNATIVE SIGNALS TO RAS FOR HEMATOPOIETIC TRANSFORMATION BY THE BCR-ABL ONCOGENE

Biological function of the BCR-ABL oncogene is dependent on its activa ted tyrosine kinase. Mutations that Inactivate the SRC homology 2 (SH2 ) domain, the GRB2-binding site in BCR, or the major autophosphorylati on site of the kinase domain selectively disrupt downstream signaling but not tyrosine kinase activity. Despite a loss of fibroblast transfo rmation activity, all three mutants retain the ability to render hemat opoietic cell lines growth factor independent and transform primary bo ne marrow cells in vitro. In vivo tests of malignant potential reveal a most critical role for signals dependent on the BCR-ABL SH2 domain. The efficiency of both fibroblast and hematopoietic transformation by BCR-ABL is strongly affected by increased dosage of the SHC adapter pr otein, which can connect tyrosine kinase signals to RAS. The BCR-ABL o ncogene activates multiple alternative pathways to RAS for hematopoiet ic transformation.