ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition.
ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition.
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作者：
Ju HQ;Zhan G;Huang A;Sun Y;Wen S;Yang J;Lu WH;Xu RH;Li J;Li Y;Garcia-Manero G;Huang P;Hu Y
fms样酪氨酸激酶3基因（FLT3/ITD）内部串联重复（ITD）突变在急性髓性白血病（AML）中是一种不利的遗传改变，与不良预后相关。代谢改变参与了肿瘤的进展，并作为治疗干预的靶点引起了人们的兴趣。然而，很少有研究分析FLT3/ITD突变背景下细胞代谢的适应性。在这里，我们报道FLT3/ITD通过akt介导的线粒体己糖激酶（HK2）上调导致有氧糖酵解显著增加，并使白血病细胞高度依赖糖酵解，并且对糖酵解活性的药物抑制敏感。抑制糖酵解优先导致FLT3/ITD白血病细胞严重的ATP消耗和大量细胞死亡。糖酵解抑制剂显著增强FLT3酪氨酸激酶抑制剂索拉非尼诱导的细胞毒性。重要的是，这种组合在携带FLT3/ITD白血病的小鼠模型中提供了实质性的治疗益处。我们的研究表明FLT3/ITD突变促进Warburg效应，这种代谢改变可以通过代谢干预制定有效的治疗策略来治疗FLT3/ITD突变的AML。
Internal tandem duplication (ITD) mutation in Fms-like tyrosine kinase 3 gene (FLT3/ITD) represents an unfavorable genetic change in acute myeloid leukemia (AML) and is associated with poor prognosis. Metabolic alterations have been involved in tumor progression and attracted interest as a target for therapeutic intervention. However, few studies analyzed the adaptations of cellular metabolism in the context of FLT3/ITD mutation. Here, we report that FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity. Inhibition of glycolysis preferentially causes severe ATP depletion and massive cell death in FLT3/ITD leukemia cells. Glycolytic inhibitors significantly enhances the cytotoxicity induced by FLT3 tyrosine kinase inhibitor sorafenib. Importantly, such combination provides substantial therapeutic benefit in a murine model bearing FLT3/ITD leukemia. Our study suggests that FLT3/ITD mutation promotes Warburg effect, and such metabolic alteration can be exploited to develop effective therapeutic strategy for treatment of AML with FLT3/ITD mutation via metabolic intervention.
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