title: CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells.
abstract: Chronic myelogenous leukemia (CML) is driven by constitutively activated Bcr-Abl tyrosine kinase, which causes the defective adhesion of CML cells to bone marrow stroma. The overexpression of p210Bcr-Abl was reported to down-regulate CXCR4 expression, and this is associated with the cell migration defects in CML. We proposed that tyrosine kinase inhibitors, imatinib or INNO-406, may restore CXCR4 expression and cause the migration of CML cells to bone marrow microenvironment niches, which in turn results in acquisition of stroma-mediated chemoresistance of CML progenitor cells. In KBM5 and K562 cells, imatinib, INNO-406, or IFN-alpha increased CXCR4 expression and migration. This increase in CXCR4 levels on CML progenitor cells was likewise found in samples from CML patients treated with imatinib or IFN-alpha. Imatinib induced G0-G1 cell cycle block in CML cells, which was further enhanced in a mesenchymal stem cell (MSC) coculture system. MSC coculture protected KBM-5 cells from imatinib-induced cell death. These antiapoptotic effects were abrogated by the CXCR4 antagonist AMD3465 or by inhibitor of integrin-linked kinase QLT0267. Altogether, these findings suggest that the up-regulation of CXCR4 by imatinib promotes migration of CML cells to bone marrow stroma, causing the G0-G1 cell cycle arrest and hence ensuring the survival of quiescent CML progenitor cells.
authors.affiliation: Department of Clinical Pathology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Linhua
authors.initials: L
authors.lastname: Jin
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tabe
authors.forename: Sergej
authors.initials: S
authors.lastname: Konoplev
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Clinton E
authors.initials: CE
authors.lastname: Leysath
authors.forename: Hongbo
authors.initials: H
authors.lastname: Lu
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Akimichi
authors.initials: A
authors.lastname: Ohsaka
authors.forename: Mary-Beth
authors.initials: MB
authors.lastname: Rios
authors.forename: Leslie
authors.initials: L
authors.lastname: Calvert
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D001549:Benzamides; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D016898:Interferon-alpha / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018952:Antigens, CD34; D001549:Benzamides; D016898:Interferon-alpha; D010879:Piperazines; D011743:Pyrimidines; D019718:Receptors, CXCR4; D000068877:Imatinib Mesylate