Homoharringtonine Synergized with Gilteritinib Results in the Downregulation of Myeloid Cell Leukemia-1 by Upregulating UBE2L6 in FLT3-ITD-Mutant Acute Myeloid (Leukemia) Cell Lines

Jiayi Cai; Honghui Huang; Xiaoli Hu; Wenjing Lang; Wanbin Fu; Lan Xu; Zilong Qiu; Hua Zhong; Fangyuan Chen

doi:10.1155/2021/3766428

Homoharringtonine Synergized with Gilteritinib Results in the Downregulation of Myeloid Cell Leukemia-1 by Upregulating UBE2L6 in FLT3-ITD-Mutant Acute Myeloid (Leukemia) Cell Lines

J Oncol. 2021 Sep 21:2021:3766428. doi: 10.1155/2021/3766428. eCollection 2021.

Authors

Jiayi Cai¹, Honghui Huang², Xiaoli Hu³, Wenjing Lang², Wanbin Fu², Lan Xu², Zilong Qiu⁴, Hua Zhong², Fangyuan Chen²

Affiliations

¹ Department of Central Lab, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
² Department of Hematology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
³ Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.
⁴ Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China.

Abstract

FMS-like tyrosine kinase 3 (FLT3) mutant acute myeloid leukemia (AML) occurs in approximately 30% of all AML patients and still has a poor prognosis. This study is directed to investigate gilteritinib in combination with homoharringtonine (HHT) on FLT3-ITD-mutant AML cell lines. In our study, we found that cell proliferation was dramatically suppressed by the combination of gilteritinib and HHT. This combination therapy decreased the mitochondrial membrane potential, finally inducing apoptosis. We demonstrated that gilteritinib downregulated the expression of FLT3 and downstream signaling, further decreased the mRNA level of myeloid cell leukemia-1 (Mcl-1). HHT and combination therapy could upregulate UBE2L6, which induced the degradation of Mcl-1 via ubiquitin-proteasome system. Knockdown of UBE2L6 could protect Mcl-1 from deprivation through the ubiquitin-proteasome system. These findings may provide a novel theoretical basis for the treatment of AML patients with FLT3-ITD mutations.