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- Title
p210<sup>Bcr−Abl</sup> desensitizes Cdc42 GTPase signaling for SDF-1α-directed migration in chronic myeloid leukemia cells.
- Authors
Chang, Y.-C.; Tien, S.-C.; Tien, H.-F.; Zhang, H.; Bokoch, G. M.; Chang, Z.-F.
- Abstract
Chronic myeloid leukemia (CML) is a lethal hematological disorder caused by the p210Bcr−Abl oncogene. Previous studies have suggested that p210Bcr−Abl 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 p210Bcr−Abl, this study aimed to determine whether p210Bcr−Abl 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 p210Bcr−Abl-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 p210Bcr−Abl 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 p210Bcr−Abl 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.
- Subjects
CHRONIC myeloid leukemia; ONCOGENES; CYTOSKELETON; BONE marrow; CHEMOTAXIS; PROTEIN-tyrosine kinases
- Publication
Oncogene, 2009, Vol 28, Issue 46, p4105
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2009.260