BCR ABL-MEDIATED LEUKEMOGENESIS REQUIRES THE ACTIVITY OF THE SMALL GTP-BINDING PROTEIN RAC/

The phenotype of hematopoietic cells transformed by the BCR/ABL oncopr otein of the Philadelphia chromosome is characterized by growth factor -independent proliferation, reduced susceptibility to apoptosis, and a ltered adhesion and motility. The mechanisms underlying this phenotype are not fully understood, but there is evidence that some of the prop erties of BCR/ABL-expressing cells are dependent on the activation of downstream effector molecules such as RAS, PI-3k, and bcl-2, We show h ere that the small GTP-binding protein Rac is activated by BCR/ABL in a tyrosine kinase-dependent manner. Upon transfection with a vector ca rrying the dominant-negative N17Rac, BCR/ABL-expressing myeloid precur sor 32Dcl3 cells retained the resistance to growth factor deprivation- induced apoptosis but showed a decrease in proliferative potential in the absence of interleukin-3 (IL-3) and markedly reduced invasive prop erties. Moreover, compared with BCR/ABL-expressing cells, fewer BCR/AB L plus N17Rac double transfectants were capable of homing to bone marr ow and spleen. Consistent with these findings, survival of SCID mice i njected with the BCR/ABL plus N17Rac double transfectants was markedly prolonged as compared with that of mice injected with BCR/ABL-express ing cells. Together, these data support the important role of a Rac-de pendent pathway(s) controlling motility in BCR/ABL-mediated leukemogen esis.