Reduced oncogenicity of p190 Bcr/Abl F-actin-binding domain mutants

The deregulated Bcr/Abl tyrosine kinase is responsible for the development of Philadelphia (Ph)-positive leukemia in humans. To investigate the signif icance of the C-terminal Abl actin-binding domain within Bcr/Abl p190 in th e development of leukemia/lymphoma in vivo, mutant p190 DNA constructs were used to generate transgenic mice, Eight founder and progeny mice of 5 diff erent lines were monitored for leukemogenesis. Latency was markedly increas ed and occurrence decreased in the p190 del C lines as compared with nonmut ated p190 BCR/ABL transgenics. Western blot analysis of involved hematologi c tissues of the p190 del C transgenics with end-stage disease showed high- level expression of the transgene and tyrosine phosphorylation of Cbl and H ef1/Cas, proteins previously shown to be affected by Bcr/Abl, These results show that the actin-binding domain of Abl enhances leukemia development bu t does not appear to be an absolute requirement for leukemogenesis. (Blood. 2000;96: 2226-2232) (C) 2000 by The American Society of Hematology.