The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization

Ward, Patrick S.; Lü, Chao; Cross, Justin R.; Abdel-Wahab, Omar; Levine, Ross L.; Schwartz, Gary K.; Thompson, Craig B.

doi:10.1074/jbc.m112.435495

Cited by 151 publications

(166 citation statements)

References 47 publications

(50 reference statements)

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“…Previous in vitro studies have shown that overexpression of IDH2R140Q and IDH2R172K in cell lines resulted in different levels of 2HG production, with IDH2R172K being more efficient than IDH2R140Q. This work also showed that the subcellular localization of the mutant enzyme can affect 2HG production, because relocalization of mutant IDH1 from the cytosol to the mitochondria dramatically increased 2HG production (28). However, studying the quantitative effects of IDH mutant proteins using overexpression systems has drawbacks, because 2HG production is influenced by the level of protein expression, which is often not physiological in these model systems.…”

Section: Discussionsupporting

confidence: 52%

“…This effect has been observed in previous in vitro work where 2HG production by overexpressed (each KI was compared with WT) were performed, and *P < 0.05, **P < 0.01, and ***P < 0.001. IDH1R132H depended on the expression level of both WT and mutant proteins (28). Given this biological complexity, more accurate in vivo models should be more informative in determining the critical differences in the effects of specific IDH mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Dot blotting to detect 5hmC was performed as described (28). Briefly, genomic DNA was prepared from FACS-sorted CD3 + T cells isolated from IDH1R132H, IDH2R140Q, IDH2R172K, and WT mice by using the Nucleospin Tissue kit (Macherey-Nagel).…”

Section: Idh2mentioning

confidence: 99%

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The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

Lemonnier

Cairns

Inoue

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic isocitrate dehydrogenase (IDH)1 and IDH2 mutations at three hotspot arginine residues cause an enzymatic gain of function that leads to the production and accumulation of the metabolite 2-hydroxyglutarate (2HG), which contributes to the development of a number of malignancies. In the hematopoietic system, mutations in IDH1 at arginine (R) 132 and in IDH2 at R140 and R172 are commonly observed in acute myeloid leukemia, and elevated 2HG is observed in cells and serum. However, in angioimmunoblastic T-cell lymphoma (AITL), mutations are almost exclusively restricted to IDH2 R172, and levels of 2HG have not been comprehensively measured. In this study, we investigate the expression pattern of mutant IDH2 in the AITL tumor microenvironment and measure levels of 2HG in tissue and serum of AITL patients. We find that mutant IDH2 expression is restricted to the malignant T-cell component of AITL, and that 2HG is elevated in tumor tissue and serum of patients. We also investigate the differences between the three hotspot mutation sites in IDH1 and IDH2 using conditional knock-in mouse models. These studies show that in the lymphoid system, mutations in IDH2 at R172 produce high levels of 2HG compared with mutations at the other two sites and that lymphoid development is impaired in these animals. These data provide evidence that IDH2 R172 mutations may be the only variants present in AITL because of their capacity to produce significant amounts of the oncometabolite 2HG in the cell of origin of this disease.isocitrate dehydrogenase | AITL | lymphoma | 2-hydroxyglutarate | T cell

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

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The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

Lemonnier

Cairns

Inoue

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This exclusivity is highly interesting, but the reason is currently not clear. Studies by others have shown that mutations differ quantitatively in 2-HG production 33,46 ; this raises the possibility that different tumor types may favor certain ranges of 2-HG concentrations. In previous studies, 33 R172 is frequently the only mutation detected, 47 again suggesting biological differences.…”

Section: R140mentioning

confidence: 99%

IDH2 R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma

Wang

McKeithan

Gong

et al. 2015

Blood

199

144

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Key Points• IDH2R172 mutations define a unique subgroup with distinct T FH -like gene expression signatures in AITL.• IDH2 R172 mutations can induce DNA and repressive histone hypermethylation in AITL.Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A, and isocitrate dehydrogenase 2 (IDH2). Although IDH2 mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2

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“…However, it is only the concentration and not the production of (R)‐2HG which is nonphysiological in IDH ‐mutated tumors, as it is also produced as a minor product by αKG reductase enzymes and is oxidized back to αKG by 2HG dehydrogenases 102. Interestingly, cells expressing mutant IDH1 produce less (R)‐2HG than those with IDH2 mutations 103. Moreover, (R)‐2HG expression by mutant IDH1 is enhanced by the co‐expression of wild‐type IDH1, leading to the formation of heterodimers 100, 103.…”

Section: Mutations Of Mitochondrial (And Associated) Metabolic Enzymementioning

confidence: 99%

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

Hollinshead

Tennant

2016

WIREs Mechanisms of Disease

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Mitochondria are metabolic hubs within mammalian cells and demonstrate significant metabolic plasticity. In oxygenated environments with ample carbohydrate, amino acid, and lipid sources, they are able to use the tricarboxylic acid cycle for the production of anabolic metabolites and ATP. However, in conditions where oxygen becomes limiting for oxidative phosphorylation, they can rapidly signal to increase cytosolic glycolytic ATP production, while awaiting hypoxia‐induced changes in the proteome mediated by the activity of transcription factors such as hypoxia‐inducible factor 1. Hypoxia is a well‐described phenotype of most cancers, driving many aspects of malignancy. Improving our understanding of how mitochondria change their metabolism in response to this stimulus may therefore elicit the design of new selective therapies. Many of the recent advances in our understanding of mitochondrial metabolic plasticity have been acquired through investigations of cancer‐associated mutations in metabolic enzymes, including succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. This review will describe how metabolic perturbations induced by hypoxia and mutations in these enzymes have informed our knowledge in the control of mitochondrial metabolism, and will examine what this may mean for the biology of the cancers in which these mutations are observed. WIREs Syst Biol Med 2016, 8:272–285. doi: 10.1002/wsbm.1334For further resources related to this article, please visit the WIREs website.

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The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization

Cited by 151 publications

References 47 publications

The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

IDH2 R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

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