Hong Chih-Chen, Lay Jong-Ding, Huang Jhy-Shrian, Cheng Ann-Lii, Tang Jih-Luh, Lin Ming-Tseh, Lai Gi-Ming, Chuang Shuang-En
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
Cancer Lett. 2008 Sep 18;268(2):314-24. doi: 10.1016/j.canlet.2008.04.017. Epub 2008 May 27.
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.
通过对来自同一患者的敏感和难治性白血病中差异表达的蛋白酪氨酸激酶进行新型分析，我们发现AXL在耐药白血病中上调。此外，化疗药物可在急性髓系白血病U937细胞中诱导AXL表达，且这种诱导依赖于AXL启动子的CCWGG甲基化状态。在异位过表达AXL的U937细胞中，添加外源性Gas6可诱导AXL磷酸化以及Akt和ERK1/2存活通路的激活。耐药的Gas6-AXL激活途径与Bcl-2和Twist表达增加有关。这些结果表明，在Gas6刺激存在的情况下，化疗引起的AXL上调可能诱导急性髓系白血病产生耐药性。
