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

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.

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Acknowledgements

We are grateful to Dr RB Arlinghaus (Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA) for providing 32Dp210 and WEHI cells. We thank the staff of the Second Core Lab, Department of Medical Research, National Taiwan University Hospital for technical support during this study. This study is supported by grant NSC 96-3112-B-002-006 and NSC 97-3112-B-002-026 from the National Science Council, Taiwan.

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Correspondence to Z -F Chang.

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Chang, YC., Tien, SC., Tien, HF. et al. p210Bcr−Abl desensitizes Cdc42 GTPase signaling for SDF-1α-directed migration in chronic myeloid leukemia cells. Oncogene 28, 4105–4115 (2009). https://doi.org/10.1038/onc.2009.260

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