Reactivating PP2A by FTY720 as a Novel therapy for AML with C-KIT tyrosine kinase domain mutation
Reactivating PP2A by FTY720 as a Novel therapy for AML with C-KIT tyrosine kinase domain mutation
复制标题
DOI：
10.1002/jcb.24003
复制
发表时间：
2012-04-01
影响因子：
4
通讯作者：
Huang, Shiang
中科院分区：
文献类型：
--
作者：
Yang, Yan;Huang, Qing;Huang, Shiang
受体酪氨酸激酶C-KIT的酪氨酸激酶域(TKD)突变与急性髓系白血病(AML)预后不良有关。然而，其潜在的机制还没有完全被理解。我们发现，在携带C-KIT/D816V的AML亚群和携带C-KIT/N822K突变的AML细胞系Kasumi-1中，人类肿瘤抑制因子蛋白磷酸酶2A(PP2A)的活性显著降低。用PP2A激活剂FTY720处理原代AML细胞和不同的AML细胞系。FTY720对所有白血病细胞均有毒性作用，尤其是对含有C-kit/TKD突变的细胞。此外，FTY720对AML白血病细胞的毒性是通过PP2A活性的恢复、PP2A抑制剂SET的下调、PP2A-CTYR307的去磷酸化以及相关的PP2A亚单位A和B55a的上调而实现的。我们的研究表明，存在C-KIT/TKD突变的AML患者的PP2A活性降低，可能使PP2A活性的恢复成为治疗C-KIT/TKD突变的AML患者的新方法。J.细胞。生物化学。2012年，113：13141322。(C)2011年威利期刊公司。
The tyrosine kinase domain (TKD) mutations of receptor tyrosine kinase C-KIT are associated with a poor prognosis in acute myeloid leukemia (AML). However, the underlying mechanisms are not fully understood. We found the activity of protein phosphatase 2A (PP2A), a human tumor suppressor whose dysfunction contributes to malignant cell behavior, was significantly decreased in AML subgroups harboring C-KIT/D816V and AML cell line Kasumi-1 bearing C-KIT/N822K mutation. Primary AML cells and various AML cell lines were treated with PP2A activator FTY720. FTY720 showed a toxic effect in all leukemic cells, especially for cells harboring C-KIT/TKD mutation. Furthermore, FTY720-induced toxicity in AML leukemic cells was mediated by restoration of PP2A activity, via down-regulation of PP2A inhibitor SET, dephosporylation of PP2A-CTYR307, and up-regulation of relevant PP2A subunit A and B55a. Our research indicates that the decreased PP2A activity in AML harboring C-KIT/TKD mutation may make the restoration of PP2A activity a novel therapy for AML patients with C-KIT/TKD mutation. J. Cell. Biochem. 113: 13141322, 2012. (c) 2011 Wiley Periodicals, Inc.