The combination effect of homoharringtonine and ibrutinib on FLT3-ITD mutant acute myeloid leukemia.
The combination effect of homoharringtonine and ibrutinib on FLT3-ITD mutant acute myeloid leukemia.
复制标题
高三尖杉酯碱联合依鲁替尼对FLT3-ITD突变型急性髓系白血病的治疗作用
DOI：
10.18632/oncotarget.14463
复制
发表时间：
2017-02-21
期刊：
影响因子：
--
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Li X;Yin X;Wang H;Huang J;Yu M;Ma Z;Li C;Zhou Y;Yan X;Huang S;Jin J
急性髓系白血病（AML）是一种高度异质性的疾病，FMS样酪氨酸激酶-3（FLT 3-ITD）的内部串联重复突变对预后有负面影响。迫切需要找到有效的治疗方案。本研究探讨高三尖杉酯碱（HHT）联合伊曲替尼对FLT 3-ITD突变AML细胞的抑制作用及其机制。因此，我们观察到当伊鲁替尼与HHT组合时，在MV 4 -11和MOLM-13白血病细胞中抑制细胞增殖、诱导凋亡和将细胞周期阻滞在G 0/G1期的协同抑制作用。结果表明，联合作用的机制主要是通过调节STAT 5/Pim-2/C-Myc通路、AKT通路和Bcl-2家族，激活p21 WAF 1/CIP 1和抑制CCND/CDK复合蛋白。有趣的是，伊曲替尼和HHT的协同细胞毒性依赖于FLT 3和BTK。在这里，我们为FLT 3-ITD突变的AML患者的治疗提供了一种新的有效的治疗方法。
Acute myeloid leukemia (AML) is a highly heterogeneous disease and internal tandem duplication mutation in FMS-like tyrosine-kinase-3 (FLT3-ITD) has a negative impact on outcome. Finding effective treatment regimens is desperately needed. In this study, we explored the inhibitory effect and mechanism of homoharringtonine (HHT) in combination with ibrutinib on FLT3-ITD mutant AML cells. Consequently, we observed a synergistic inhibitory effect when ibrutinib was combined with HHT to inhibit cell proliferation, induce apoptosis and arrest cell cycle at G0/G1 phase in MV4-11 and MOLM-13 leukemia cells. Our results indicate that the mechanisms of the combination effect are mainly via regulating the STAT5/Pim-2/C-Myc pathway, AKT pathway and Bcl-2 family, activating p21WAF1/CIP1 and inhibiting CCND/CDK complex protein. Interestingly, synergistic cytotoxicity of ibrutinib and HHT was dependent on both FLT3 and BTK. Here we provide a novel effective therapeutic approach for the treatment of AML patients with FLT3-ITD mutation.