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

Autor:	Chen D; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Xia S; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Zhang R; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA; Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Li Y; Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Famulare CA; Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Fan H; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA; Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Wu R; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA; Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Wang M; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Zhu AC; Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA., Elf SE; The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA., Su R; Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA., Dong L; Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA., Arellano M; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Blum WG; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Mao H; Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Lonial S; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Stock W; Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Odenike O; Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Le Beau M; Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Boggon TJ; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA., He C; Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA., Chen J; Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA., Gao X; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA; Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. Electronic address: xgao30@uchicago.edu., Levine RL; Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: leviner@mskcc.org., Chen J; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA; Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. Electronic address: jingchen@medicine.bsd.uchicago.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2021 Sep 16; Vol. 81 (18), pp. 3833-3847.e11. Date of Electronic Publication: 2021 Jul 20.
DOI:	10.1016/j.molcel.2021.06.027
Abstrakt:	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. Competing Interests: Declaration of interests R.L.L. is on the supervisory board of QIAGEN and is a scientific advisor to Loxo, Imago, C4 Therapeutics, and Isoplexis, each of which includes an equity interest. He receives research support from and consulted for Celgene and Roche, has received research support from Prelude Therapeutics, and has consulted for Incyte, Novartis, Astellas, Morphosys, and Janssen. He has received honoraria from Lilly and Amgen for invited lectures and from Gilead for grant reviews. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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