title: p210(Bcr-Abl) desensitizes Cdc42 GTPase signaling for SDF-1alpha-directed migration in chronic myeloid leukemia cells.
abstract: 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-1alpha (SDF-1alpha). 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-1alpha chemotaxis through Rho GTPase signaling. We found that SDF-1alpha stimulated Cdc42 GTPase activation in myeloid progenitor 32D, but not in p210(Bcr-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 p210(Bcr-Abl) kinase activity decreased basal Cdc42 activity and restored SDF-1alpha-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-1alpha-chemotactic response due to desensitization of the actin polarization signal required for directional migration.
authors.affiliation: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Chang
authors.forename: S-C
authors.initials: SC
authors.lastname: Tien
authors.forename: H-F
authors.initials: HF
authors.lastname: Tien
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: G M
authors.initials: GM
authors.lastname: Bokoch
authors.forename: Z-F
authors.initials: ZF
authors.lastname: Chang
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D047428:Protein Kinase Inhibitors; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; D016044:Fusion Proteins, bcr-abl; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein