p210Bcr-Abl desensitizes Cdc42 GTPase signaling for SDF-1α-directed migration in chronic myeloid leukemia cells

Chronic myeloid leukemia (CML) is a lethal hematological disorder caused by the p210(Bcr-Abl) oncogene. Previous studies have suggested that p210(Bcr-Abl) transformation contributes to homing and retention defects, typical of immature myeloid cells in CML, by attenuating chemotactic response to stromal-derived factor-1 alpha (SDF-1 alpha). As Rho family GTPases are key regulators of the cytoskeleton and have been previously found to interact with p210(Bcr-Abl), this study aimed to determine whether p210(Bcr-Abl) signaling affects SDF-1 alpha chemotaxis through Rho GTPase signaling. We found that SDF-1 alpha stimulated Cdc42 GTPase activation in myeloid progenitor 32D, but not in p210(BcrAbl)-transformed (32Dp210) cells. In fact, the basal level of active Cdc42 was elevated in 32Dp210 cells and mononuclear cells isolated from bone marrow of CML patients. Inhibition of p210(Bcr-Abl) kinase activity decreased basal Cdc42 activity and restored SDF-1 alpha-induced Cdc42 and migration responses. Transduction of active Tat-Cdc42V12 abolished this reconstituted chemotactic response. As Cdc42 is particularly important in cytoskeletal remodeling and directional sensing, these results suggest that sustained activation of Cdc42 GTPase through p210(Bcr-Abl) tyrosine kinase signaling in CML cells contributes to defects in SDF-1 alpha-chemotactic response due to desensitization of the actin polarization signal required for directional migration. Oncogene (2009) 28, 4105-4115; doi:10.1038/onc.2009.260; published online 31 August 2009