BCR/ABL-mediated leukemogenesis requires the activity of the small GTP-binding protein Rac

• DOI: 10.1073/pnas.95.20.11858
• Publication Date: 2002-07-26T14:35:50Z
• Authors: Tomasz Skorski; Pawel Wlodarski; Laurence Daheron; Paolo Salomoni; Malgorzata Niebor...; Miroslaw Majewski; Mariusz Wasik; Bruno Calabretta
• Keywords: breakpoint cluster region; ABL; K562 cells; Homing (biology); Philadelphia chromosome

The phenotype of hematopoietic cells transformed by the BCR/ABL oncoprotein Philadelphia chromosome is characterized growth factor-independent proliferation, reduced susceptibility to apoptosis, and altered adhesion motility. mechanisms underlying this are not fully understood, but there evidence that some properties BCR/ABL-expressing dependent on activation downstream effector molecules such as RAS, PI-3k, bcl-2. We show here small GTP-binding protein Rac activated in a tyrosine kinase-dependent manner. Upon transfection with vector carrying dominant-negative N17Rac, myeloid precursor 32Dcl3 retained resistance factor deprivation-induced apoptosis showed decrease proliferative potential absence interleukin-3 (IL-3) markedly invasive properties. Moreover, compared cells, fewer plus N17Rac double transfectants were capable homing bone marrow spleen. Consistent these findings, survival SCID mice injected was prolonged cells. Together, data support important role Rac-dependent pathway(s) controlling motility BCR/ABL-mediated leukemogenesis.