Li Xia, Yin Xiufeng, Wang Huafeng, Huang Jiansong, Yu Mengxia, Ma Zhixin, Li Chenying, Zhou Yile, Yan Xiao, Huang ShuJuan, Jin Jie
Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.
Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Oncotarget. 2017 Feb 21;8(8):12764-12774. doi: 10.18632/oncotarget.14463.
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.
急性髓系白血病（AML）是一种高度异质性疾病，FMS样酪氨酸激酶3（FLT3-ITD）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。在本研究中，我们探讨了高三尖杉酯碱（HHT）联合依鲁替尼对FLT3-ITD突变AML细胞的抑制作用及机制。结果发现，依鲁替尼与HHT联合使用时，对MV4-11和MOLM-13白血病细胞的增殖具有协同抑制作用，可诱导细胞凋亡并使细胞周期停滞于G0/G1期。我们的结果表明，联合作用机制主要是通过调节STAT5/Pim-2/C-Myc通路、AKT通路和Bcl-2家族，激活p21WAF1/CIP1并抑制CCND/CDK复合蛋白。有趣的是，依鲁替尼和HHT的协同细胞毒性依赖于FLT3和BTK。我们在此为治疗FLT3-ITD突变的AML患者提供了一种新的有效治疗方法。
