高三尖杉酯碱联合Gilteritinib通过上调UBE2L6降解Mcl-1在FLT3-ITD突变急性髓系白血病细胞中的协同作用

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.