Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability.
Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability.
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DOI：
10.1038/s41467-022-29639-0
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发表时间：
2022-04-19
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
不同遗传亚型的急性髓系白血病(AML)的代谢程序可能有很大不同。这些程序不是静态的实体，但可以随着细胞外的变化或对途径抑制药物的反应而迅速改变。在这里，我们发现具有Flt3内部串联重复(Flt3-ITD+)的AML患者的特征是琥珀酸-CoA连接酶的高表达和线粒体电子传递链(ETC)复合体II的高活性，从而推动与Krebs循环相关的高线粒体呼吸活动。在抑制ETC复合体II促进Flt3-ITD+AML细胞凋亡的同时，细胞也通过从细胞外微环境输入乳酸来快速适应。13C3标记的乳酸代谢通量分析表明，AML细胞利用乳酸作为线粒体呼吸的燃料。通过阻断单羧酸转运体1(MCT1)来抑制乳酸转运，在体外和体内都能显著增强对ETC复合体II抑制的敏感性。我们的研究强调了癌细胞的代谢适应性，可以用于治疗。对特定代谢途径的抑制通常会推动代谢适应。在这里，作者证明了Flt3-ITD + 急性髓系白血病细胞是由氧磷酶驱动的，抑制复合体II的活性会导致乳酸内流增加以驱动呼吸，这造成了一个有针对性的脆弱性。
Metabolic programs can differ substantially across genetically distinct subtypes of acute myeloid leukemia (AML). These programs are not static entities but can change swiftly as a consequence of extracellular changes or in response to pathway-inhibiting drugs. Here, we uncover that AML patients with FLT3 internal tandem duplications (FLT3-ITD+) are characterized by a high expression of succinate-CoA ligases and high activity of mitochondrial electron transport chain (ETC) complex II, thereby driving high mitochondrial respiration activity linked to the Krebs cycle. While inhibition of ETC complex II enhances apoptosis in FLT3-ITD+ AML, cells also quickly adapt by importing lactate from the extracellular microenvironment. 13C3-labelled lactate metabolic flux analyses reveal that AML cells use lactate as a fuel for mitochondrial respiration. Inhibition of lactate transport by blocking Monocarboxylic Acid Transporter 1 (MCT1) strongly enhances sensitivity to ETC complex II inhibition in vitro as well as in vivo. Our study highlights a metabolic adaptability of cancer cells that can be exploited therapeutically. Inhibition of specific metabolic pathways often drives metabolic adaptation. Here, the authors show that FLT3-ITD + acute myeloid leukemia cells are OXPHOS-driven, and inhibition of complex II activity results in increased lactate influx to drive respiration, which creates a targetable vulnerability.
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影响因子：
50.3
作者：
Jones CL;Stevens BM;D'Alessandro A;Reisz JA;Culp-Hill R;Nemkov T;Pei S;Khan N;Adane B;Ye H;Krug A;Reinhold D;Smith C;DeGregori J;Pollyea DA;Jordan CT
通讯作者：
Jordan CT
影响因子：
14.8
作者：
Chen YJ;Mahieu NG;Huang X;Singh M;Crawford PA;Johnson SL;Gross RW;Schaefer J;Patti GJ
通讯作者：
Patti GJ
影响因子：
11.4
作者：
Horton, S. J.;Jaques, J.;Schuringa, J. J.
通讯作者：
Schuringa, J. J.
影响因子：
20.3
作者：
Chen, Wen-Lian;Wang, Jing-Han;Jia, Wei
通讯作者：
Jia, Wei
影响因子：
16.6
作者：
Erdem A;Marin S;Pereira-Martins DA;Cortés R;Cunningham A;Pruis MG;de Boer B;van den Heuvel FAJ;Geugien M;Wierenga ATJ;Brouwers-Vos AZ;Rego EM;Huls G;Cascante M;Schuringa JJ
通讯作者：
Schuringa JJ