Lysine acetylation restricts mutant IDH2 activity to optimize transformation in AML cells

• Published in: Molecular cell 2021-09, Vol.81 (18), p.3833-3847.e11
• Main Authors: Chen, Dong, Xia, Siyuan, Zhang, Rukang, Li, Yuancheng, Famulare, Christopher A., Fan, Hao, Wu, Rong, Wang, Mei, Zhu, Allen C., Elf, Shannon E., Su, Rui, Dong, Lei, Arellano, Martha, Blum, William G., Mao, Hui, Lonial, Sagar, Stock, Wendy, Odenike, Olatoyosi, Le Beau, Michelle, Boggon, Titus J., He, Chuan, Chen, Jianjun, Gao, Xue, Levine, Ross L., Chen, Jing
• Format: Article
• Language: English
• Subjects: 2-HG; ACAT1; AML; dimerization; FLT3; K413 acetylation; mutant IDH2; SIRT3
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.06.027

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. [Display omitted] •Different intracellular concentrations of 2-HG have different cellular functions•K413 acetylation inhibits mutant IDH2 in AML cells by attenuating dimerization•Restricted mutant IDH2 produces sufficient oncometabolite 2-HG for transformation•K413 acetylation of mutant IDH2 avoids cytotoxic accumulation of intracellular 2-HG Oncometabolite 2-hydroxyglutarate (2-HG) has been reported to suppress transformation in AML cells. In this article, Chen et al. report that different intracellular concentrations of 2-HG correlate with its different cellular functions, while inhibitory K413 acetylation optimizes leukemogenic ability of mutant IDH2 in AML cells by both producing sufficient 2-HG for transformation and avoiding cytotoxic accumulation of intracellular 2-HG.