Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia

Cancer Lett. 2008 Sep 18;268(2):314-24. doi: 10.1016/j.canlet.2008.04.017. Epub 2008 May 27.

Abstract

By using a novel profiling analysis of protein tyrosine kinases differentially expressed in the sensitive and refractory leukemia from the same patients we found that AXL was upregulated in drug-resistant leukemia. Furthermore, AXL could be induced by chemotherapy drugs in the acute myeloid leukemia U937 cells and this induction was dependent on the CCWGG methylation status of the AXL promoter. In U937 cells ectopically overexpressing AXL, addition of exogenous Gas6 induced AXL phosphorylation and activation of the Akt and ERK1/2 survival pathways. The Gas6-AXL activation pathway of drug resistance was associated with increased expression of Bcl-2 and Twist. These results show that upregulation of AXL by chemotherapy might induce drug resistance in acute myeloid leukemia in the presence of Gas6 stimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Base Sequence
  • Drug Resistance, Neoplasm
  • Humans
  • Intercellular Signaling Peptides and Proteins / physiology
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / metabolism
  • Molecular Sequence Data
  • Oncogene Proteins / analysis
  • Oncogene Proteins / genetics
  • Oncogene Proteins / physiology*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases / analysis
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Signal Transduction
  • U937 Cells

Substances

  • Antineoplastic Agents
  • Intercellular Signaling Peptides and Proteins
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • growth arrest-specific protein 6
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase