title: Mechanisms of AXL overexpression and function in Imatinib-resistant chronic myeloid leukemia cells.
abstract: AXL is a receptor tyrosine kinase of the TAM family, the function of which is poorly understood. We previously identified AXL overexpression in Imatinib (IM)-resistant CML cell lines and patients. The present study was conducted to investigate the role of AXL and the mechanisms underlying AXL overexpression in Tyrosine Kinase Inhibitor (TKI)-resistant CML cells. We present evidence that high AXL expression level is a feature of TKI-resistant CML cells and knockdown of AXL sensitized TKI-resistant cells to IM. In addition, expression of wild-type AXL but not a dominant negative form of AXL confers IM-sensitive CML cells the capacity to resist IM effect. AXL overexpression required PKCα and β and constitutive activation of ERK1/2. Accordingly, GF109203X a PKC inhibitor, U0126 a MEK1 inhibitor and PKCα/β knockdown restore sensitivity to IM while PKCα or PKCβ overexpression in CML cells promotes protection against IM-induced cell death. Finally, using luciferase promoter activity assays we established that AXL is regulated transcriptionally through the AP1 transcription factor. Our findings reveal an unexpected role of AXL in resistance to TKI in CML cells, identify the molecular mechanisms involved in its overexpression and support the notion that AXL is a new marker of resistance to TKI in CML.
authors.affiliation: INSERM U895, Centre Méditerranéen de Médecine Moléculaire, Team Cell Death, Differentiation, Inflammation and Cancer, Nice, France.
authors.forename: Maeva
authors.initials: M
authors.lastname: Dufies
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Belhacene
authors.forename: Guillaume
authors.initials: G
authors.lastname: Robert
authors.forename: Thomas
authors.initials: T
authors.lastname: Cluzeau
authors.forename: Fréderic
authors.initials: F
authors.lastname: Luciano
authors.forename: Jill Patrice
authors.initials: JP
authors.lastname: Cassuto
authors.forename: Sophie
authors.initials: S
authors.lastname: Raynaud
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D015854:Up-Regulation; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human