Journal
ONCOTARGET
Volume 2, Issue 11, Pages 874-885Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.360
Keywords
CML; Imatinib resistance; AXL; ERK1/2; PKC
Categories
Funding
- Ligue Nationale contre le Cancer
- Fondation de France
- Ligue Nationale Contre le Cancer (Equipe Labellisee)
- INCa [PL-2010-219]
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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 PKCa and beta and constitutive activation of ERK1/2. Accordingly, GF109203X a PKC inhibitor, U0126 a MEK1 inhibitor and PKCa/beta knockdown restore sensitivity to IM while PKCa or PKC beta 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.
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