title: Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts.
abstract: We and others have previously demonstrated that p210 Bcr-Abl tyrosine kinase inhibits stromal cell-derived factor-1α/CXCR4 chemokine receptor signaling, contributing to the deficient adhesion of chronic myeloid leukemia (CML) cells to bone marrow stroma. Conversely, exposure of CML cells to a tyrosine kinase inhibitor (TKI) enhances migration of CML cells towards stromal cell layers and promotes non-pharmacological resistance to imatinib. Src-related kinase Lyn is known to interact with CXCL12/CXCR4 signaling and is directly activated by p210 Bcr-Abl. In this study, we demonstrate that TKI treatment promoted CXCR4 redistribution into the lipid raft fraction, in which it co-localized with active phosphorylated form of Lyn (LynTyr396) in CML cells. Lyn inhibition or cholesterol depletion abrogated imatinib-induced migration, and dual Src/Abl kinase inhibitor dasatinib induced fewer CML cells to migrate to the stroma. These findings demonstrate the novel mechanism of microenvironment-mediated resistance through lipid raft modulation, which involves compartmental changes of the multivalent CXCR4 and Lyn complex. We propose that pharmacological targeting of lipid rafts may eliminate bone marrow-resident CML cells through interference with microenvironment-mediated resistance.
authors: Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors: Y
authors: Y
authors: Tabe
authors: L
authors: L
authors: Jin
authors: K
authors: K
authors: Iwabuchi
authors: R-Y
authors: RY
authors: Wang
authors: N
authors: N
authors: Ichikawa
authors: T
authors: T
authors: Miida
authors: J
authors: J
authors: Cortes
authors: M
authors: M
authors: Andreeff
authors: M
authors: M
authors: Konopleva
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D015153:Blotting, Western; D054377:Chemokine CXCL12 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use*; D011485:Protein Binding; D011743:Pyrimidines / Q000627:therapeutic use*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D010879:Piperazines; D011743:Pyrimidines; D019718:Receptors, CXCR4; D000068877:Imatinib Mesylate; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases