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

Mol Cell. 2021 Sep 16;81(18):3833-3847.e11. doi: 10.1016/j.molcel.2021.06.027. Epub 2021 Jul 20.

Abstract

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.

Keywords: 2-HG; ACAT1; AML; FLT3; K413 acetylation; SIRT3; dimerization; mutant IDH2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA C-Acetyltransferase / metabolism
  • Acetylation
  • Animals
  • Antineoplastic Agents / pharmacology
  • Female
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism
  • Ketoglutaric Acids / metabolism
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Lysine / genetics
  • Lysine / metabolism
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mutation / genetics
  • NADP / metabolism
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Polymorphism, Single Nucleotide / genetics
  • Primary Cell Culture
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein-Tyrosine Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Ketoglutaric Acids
  • Nuclear Proteins
  • NADP
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • ACAT1 protein, human
  • Acetyl-CoA C-Acetyltransferase
  • Protein-Tyrosine Kinases
  • Lysine