DIFFERENTIAL COMPLEMENTATION OF BCR-ABL POINT MUTANTS WITH C-MYC

A complementation strategy was developed to define the signaling pathw ays activated by the Bcr-Abl tyrosine kinase. Transformation inactive point mutants of Bcr-Abl were tested for complementation with c-Myc. S ingle point mutations in the Src-homology 2 (SH2) domain, the major ty rosine autophosphorylation site of the kinase domain, and the Grb-2 bi nding site in the Bcr region impaired the transformation of fibroblast s by Bcr-Abl. Hyperexpression of c-Myc efficiently restored transforma tion activity only to the Bcr-Abl SH2 mutant. These data support a mod el in which Bcr-Abl activates at least two independent pathways for tr ansformation. This strategy may be useful for discerning signaling pat hways activated by other oncogenes.