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.
Highlights
A feature of chronic myeloid leukemia (CML) cells is the presence of the Philadelphia chromosome (Ph) that results from the t(9;22)(q34;q11) translocation [1]
Activation of tyrosine kinases including LYN, FYN, and AXL has been reported in IM and Nilotinib-resistant cell lines and in some CML patients treated with such inhibitors [9,10,11]
We have previously reported that AXL is overexpressed in IM-resistant CML cell lines [9, 20]
Summary
A feature of chronic myeloid leukemia (CML) cells is the presence of the Philadelphia chromosome (Ph) that results from the t(9;22)(q34;q11) translocation [1]. In CML, p210-BCR-ABL is a constitutively activated tyrosine kinase that triggers several signaling pathways which collectively confers CML cells a proliferative advantage and resistance to apoptosis [2,3,4,5]. Imatinib (IM), a tyrosine kinase inhibitor (TKI) is used frequently as the first line treatment for patients suffering CML [6, 7], even though other TKIs including Dasatinib and Nilotinib are given as a first line therapy in CML patients. Activation of tyrosine kinases including LYN, FYN, and AXL has been reported in IM and Nilotinib-resistant cell lines and in some CML patients treated with such inhibitors [9,10,11]. Targeting tyrosine kinases, expression of which is elevated in resistant patients could be a pertinent option to treat TKI-refractory patients
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