Cai Jiayi, Huang Honghui, Hu Xiaoli, Lang Wenjing, Fu Wanbin, Xu Lan, Qiu Zilong, Zhong Hua, Chen Fangyuan
Department of Central Lab, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Department of Hematology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
J Oncol. 2021 Sep 21;2021:3766428. doi: 10.1155/2021/3766428. eCollection 2021.
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.
FMS样酪氨酸激酶3（FLT3）突变型急性髓系白血病（AML）约占所有AML患者的30%，预后仍然较差。本研究旨在探讨吉瑞替尼联合高三尖杉酯碱（HHT）对FLT3-ITD突变型AML细胞系的作用。在我们的研究中，我们发现吉瑞替尼和HHT联合使用可显著抑制细胞增殖。这种联合疗法降低了线粒体膜电位，最终诱导细胞凋亡。我们证明，吉瑞替尼下调FLT3及其下游信号的表达，进一步降低髓系细胞白血病-1（Mcl-1）的mRNA水平。HHT及联合疗法可上调UBE2L6，其通过泛素-蛋白酶体系统诱导Mcl-1降解。敲低UBE2L6可保护Mcl-1不被泛素-蛋白酶体系统降解。这些发现可能为FLT3-ITD突变的AML患者的治疗提供新的理论依据。
