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.
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.
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DOI：
10.1155/2021/3766428
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发表时间：
2021
影响因子：
--
通讯作者：
Chen F
中科院分区：
文献类型：
--
作者：
Cai J;Huang H;Hu X;Lang W;Fu W;Xu L;Qiu Z;Zhong H;Chen F
FMS样酪氨酸激酶3（FLT 3）突变型急性髓性白血病（AML）发生在所有AML患者的约30%中，并且仍然具有不良预后。本研究旨在研究gilteritinib联合高三尖杉酯碱（HHT）对FLT 3-ITD突变型AML细胞系的作用。在我们的研究中，我们发现gilteritinib和HHT的组合显著抑制了细胞增殖。这种联合治疗降低了线粒体膜电位，最终诱导细胞凋亡。我们证明，gilteritinib下调FLT 3和下游信号的表达，进一步降低髓细胞白血病-1（Mcl-1）的mRNA水平。HHT和联合治疗可上调UBE 2L 6，UBE 2L 6通过泛素-蛋白酶体系统诱导Mcl-1降解。UBE 2L 6的敲除可以通过泛素-蛋白酶体系统保护Mcl-1免受剥夺。这些发现可能为FLT 3-ITD突变的AML患者的治疗提供新的理论依据。
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.
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影响因子：
20.3
作者：
Thiede, C;Steudel, C;Illmer, T
通讯作者：
Illmer, T
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20.3
作者：
Kottaridis, PD;Gale, RE;Linch, DC
通讯作者：
Linch, DC
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2.6
作者：
Chen, Chen;Xu, Wei;Yang, Jing
通讯作者：
Yang, Jing
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11.5
作者：
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通讯作者：
Ge, Yubin
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影响因子：
7.3
作者：
Zhang, Ting;Shen, Shuijie;Jin, Jie
通讯作者：
Jin, Jie