Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia.
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.
Hong
Chih-Chen
CC
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
Lay
Jong-Ding
JD
Huang
Jhy-Shrian
JS
Cheng
Ann-Lii
AL
Tang
Jih-Luh
JL
Lin
Ming-Tseh
MT
Lai
Gi-Ming
GM
Chuang
Shuang-En
SE
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D019008:Drug Resistance, Neoplasm; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D020298:U937 Cells; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722289:AXL protein, human