Mechanisms of AXL overexpression and function in Imatinib-resistant chronic myeloid leukemia cells
Metrics: PDF 4951 views | HTML 3253 views | ?
1 INSERM U895, Centre Méditerranéen de Médecine Moléculaire, Team «Cell Death, Differentiation, Inflammation and Cancer», Nice, France
2 Université de Nice Sophia Antipolis, Faculté de Médecine, Nice, France
3 Equipe labellisée par la Ligue Nationale Contre le Cancer 2011-2013, Paris, France
4 Service d’Hématologie Clinique et de Transplantation, Nice, France
5 Service d’Oncohématologie, Nice France
Received: November 24, 2011; Accepted: November 27, 2011; Published: November 30, 2011;
Keywords: CML, Imatinib resistance, AXL, ERK1/2, PKC
Dr Patrick Auberger, email:
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.