P210 BcrAbl 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 BcrAbl oncogene. Previous studies have suggested that p210 BcrAbl transformation contributes to homing and retention defects, typical of immature myeloid cells in CML, by attenuating chemotactic response to stromal-derived factor-1α (SDF-1α). As Rho family GTPases are key regulators of the cytoskeleton and have been previously found to interact with p210 BcrAbl, this study aimed to determine whether p210 BcrAbl signaling affects SDF-1α chemotaxis through Rho GTPase signaling. We found that SDF-1α 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 BcrAbl kinase activity decreased basal Cdc42 activity and restored SDF-1α-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 BcrAbl tyrosine kinase signaling in CML cells contributes to defects in SDF-1α-chemotactic response due to desensitization of the actin polarization signal required for directional migration.