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Article: Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations

TitleCancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations
Authors
Issue Date2010
Citation
Journal of Experimental Medicine, 2010, v. 207, n. 2, p. 339-344 How to Cite?
AbstractMutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel nicotinamide adenine dinucleotide phosphate (NADPH) - dependent reduction of α-ketoglutarate (α-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and α-KG. This prevents the oxidative decarboxylation of isocitrate to α-KG, and facilitates the conversion of α-KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity.
Persistent Identifierhttp://hdl.handle.net/10722/291943
ISSN
2023 Impact Factor: 12.6
2023 SCImago Journal Rankings: 6.838
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorGross, Stefan-
dc.contributor.authorCairns, Rob A.-
dc.contributor.authorMinden, Mark D.-
dc.contributor.authorDriggers, Edward M.-
dc.contributor.authorBittinger, Mark A.-
dc.contributor.authorJang, Hyun Gyung-
dc.contributor.authorSasaki, Masato-
dc.contributor.authorJin, Shengfang-
dc.contributor.authorSchenkein, David P.-
dc.contributor.authorSu, Shinsan M.-
dc.contributor.authorDang, Lenny-
dc.contributor.authorFantin, Valeria R.-
dc.contributor.authorMak, Tak W.-
dc.date.accessioned2020-11-17T14:55:26Z-
dc.date.available2020-11-17T14:55:26Z-
dc.date.issued2010-
dc.identifier.citationJournal of Experimental Medicine, 2010, v. 207, n. 2, p. 339-344-
dc.identifier.issn0022-1007-
dc.identifier.urihttp://hdl.handle.net/10722/291943-
dc.description.abstractMutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel nicotinamide adenine dinucleotide phosphate (NADPH) - dependent reduction of α-ketoglutarate (α-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and α-KG. This prevents the oxidative decarboxylation of isocitrate to α-KG, and facilitates the conversion of α-KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity.-
dc.languageeng-
dc.relation.ispartofJournal of Experimental Medicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleCancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1084/jem.20092506-
dc.identifier.pmid20142433-
dc.identifier.pmcidPMC2822606-
dc.identifier.scopuseid_2-s2.0-77149134353-
dc.identifier.volume207-
dc.identifier.issue2-
dc.identifier.spage339-
dc.identifier.epage344-
dc.identifier.eissn1540-9538-
dc.identifier.isiWOS:000274493900010-
dc.identifier.f100013411032-
dc.identifier.issnl0022-1007-

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