Mutant isocitrate dehydrogenase (IDH) 1 and 2 play a pathogenic role in cancers, including acute myeloid leukemia (AML), by producing oncometabolite 2-hydroxyglutarate (2-HG). We recently reported that tyrosine phosphorylation activates IDH1 R132H mutant in AML cells. Here, we show that mutant IDH2 (mIDH2) R140Q commonly has K413 acetylation, which negatively regulates mIDH2 activity in human AML cells by attenuating dimerization and blocking binding of substrate (α-ketoglutarate) and cofactor (NADPH). Mechanistically, K413 acetylation of mitochondrial mIDH2 is achieved through a series of hierarchical phosphorylation events mediated by tyrosine kinase FLT3, which phosphorylates mIDH2 to recruit upstream mitochondrial acetyltransferase ACAT1 and simultaneously activates ACAT1 and inhibits upstream mitochondrial deacetylase SIRT3 through tyrosine phosphorylation. Moreover, we found that the intrinsic enzyme activity of mIDH2 is much higher than mIDH1, thus the inhibitory K413 acetylation optimizes leukemogenic ability of mIDH2 in AML cells by both producing sufficient 2-HG for transformation and avoiding cytotoxic accumulation of intracellular 2-HG.

突变异柠檬酸脱氢酶 (IDH) 1 和 2 通过产生致癌代谢物 2-羟基戊二酸 (2-HG) 在癌症（包括急性髓性白血病 (AML)）中发挥致病作用。我们最近报道酪氨酸磷酸化激活 AML 细胞中的 IDH1 R132H 突变体。在这里，我们显示突变 IDH2 (mIDH2) R140Q 通常具有 K413 乙酰化，它通过减弱二聚化和阻断底物 (α-酮戊二酸) 和辅因子 (NADPH) 的结合来负调节人 AML 细胞中的 mIDH2 活性。机制上，线粒体 mIDH2 的 K413 乙酰化是通过酪氨酸激酶 FLT3 介导的一系列分级磷酸化事件实现的，其磷酸化 mIDH2 以募集上游线粒体乙酰转移酶 ACAT1，同时激活 ACAT1 并通过酪氨酸磷酸化抑制上游线粒体脱乙酰酶 SIRT3。此外，我们发现 mIDH2 的内在酶活性远高于 mIDH1，因此抑制性 K413 乙酰化通过产生足够的 2-HG 用于转化和避免细胞内 2-HG 的细胞毒性积累，优化了 mIDH2 在 AML 细胞中的白血病发生能力。