The combination effect of homoharringtonine and ibrutinib on FLT3-ITD mutant acute myeloid leukemia

// Xia Li 1, 2, * , Xiufeng Yin 1, 2, * , Huafeng Wang 1, 2 , Jiansong Huang 1, 2 , Mengxia Yu 1, 2 , Zhixin Ma 1, 2 , Chenying Li 1, 2 , Yile Zhou 1, 2 , Xiao Yan 1, 2 , ShuJuan Huang 1, 2 , Jie Jin 1, 2, 3 1 Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People’s Republic of China 2 Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China 3 Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China * These authors contributed equally to this work and share first authorship Correspondence to: Jie Jin, email: zjuhematology@163.com Keywords: acute myeloid leukemia, FLT3-ITD, homoharringtonine, ibrutinib Received: February 25, 2016 Accepted: December 25, 2016 Published: January 03, 2017 ABSTRACT 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.