This application addresses the mechanisms by which the bcr-abl chimeric oncogene causes the pathophysiologic abnormalities of chronic myelogenous leukemia. Using both routine and temperature sensitive bcr-abl transformed cell lines and a time lapse video microscopy system, the PI has found that bcr/abl induces striking abnormalities in motility. Motility was increased and disordered, and the transformed cells expressed multiple cellular projections. In addition, the PI has found increased expression of degraded forms of paxillin in bcr-abl transformed cells. The goal of the present proposal is to determine the mechanisms and significance of this unanticipated and striking finding of abnormal motility of CML cells, exploring the hypothesis that abnormal motility could contribute substantially to the phenotype of CML cells in vivo by accelerating exit from the marrow and entry into other tissues.
