Mechanisms of AXL overexpression and function in Imatinib-resistant chronic myeloid leukemia cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• AXL, a receptor tyrosine kinase in the TAM family, has an incompletely understood function.
• AXL overexpression was previously observed in Imatinib-resistant chronic myeloid leukemia (CML) cell lines and patients.

Purpose of the Study:

• To investigate the role of AXL in Tyrosine Kinase Inhibitor (TKI)-resistant CML cells.
• To elucidate the mechanisms driving AXL overexpression in TKI-resistant CML.

Main Methods:

• Knockdown of AXL in TKI-resistant CML cells.
• Expression of wild-type and dominant-negative AXL in IM-sensitive CML cells.
• Inhibition of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) pathways.
• Luciferase promoter activity assays to identify transcriptional regulation.

Main Results:

• High AXL expression is characteristic of TKI-resistant CML cells.
• AXL knockdown resensitized resistant cells to Imatinib (IM); AXL expression conferred IM resistance.
• AXL overexpression depends on PKCα/β and constitutive ERK1/2 activation.
• PKC inhibition or knockdown, and MEK1 inhibition restored IM sensitivity.
• PKCα or PKCβ overexpression protected CML cells from IM-induced death.
• AXL is transcriptionally regulated by the AP1 transcription factor.

Conclusions:

• AXL plays a significant role in TKI resistance in CML.
• AXL overexpression mechanisms involve PKC and ERK signaling pathways.
• AXL represents a potential new biomarker for TKI resistance in CML.