BCR/ABL-mediated leukemogenesis requires the activity of the small GTP-binding protein Rac.
The phenotype of hematopoietic cells transformed by the BCR/ABL oncoprotein of the Philadelphia chromosome is characterized by growth factor-independent proliferation, reduced susceptibility to apoptosis, and altered adhesion and motility. The mechanisms underlying this phenotype are not fully understood, but there is evidence that some of the properties of BCR/ABL-expressing cells are dependent on the activation of downstream effector molecules such as RAS, PI-3k, and bcl-2. We show here that the small GTP-binding protein Rac is activated by BCR/ABL in a tyrosine kinase-dependent manner. Upon transfection with a vector carrying the dominant-negative N17Rac, BCR/ABL-expressing myeloid precursor 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 properties. Moreover, compared with BCR/ABL-expressing cells, fewer BCR/ABL plus N17Rac double transfectants were capable of homing to bone marrow and spleen. Consistent with these findings, survival of SCID mice injected with the BCR/ABL plus N17Rac double transfectants was markedly prolonged as compared with that of mice injected with BCR/ABL-expressing cells. Together, these data support the important role of a Rac-dependent pathway(s) controlling motility in BCR/ABL-mediated leukemogenesis.
Skorski
T
T
Kimmel Cancer Institute, Jefferson Medical College, Blumle Life Science Building 630, 233 South 10th Street, Philadelphia, PA 19107, USA.
Wlodarski
P
P
Daheron
L
L
Salomoni
P
P
Nieborowska-Skorska
M
M
Majewski
M
M
Wasik
M
M
Calabretta
B
B
D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D002461:Cell Line, Transformed; D002465:Cell Movement; D002470:Cell Survival; D017931:DNA Primers / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007942:Leukemia, Experimental / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D020744:rac GTP-Binding Proteins
D017931:DNA Primers; D016044:Fusion Proteins, bcr-abl; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins