Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities

Cairns, Rob A.; Mak, Tak W.

doi:10.1158/2159-8290.cd-13-0083

Cited by 378 publications

(383 citation statements)

References 76 publications

(92 reference statements)

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“…2HG not only changes the metabolic state of IDH mutant cells, butcrucially -inhibits the activity of enzymes that are critical for chromatin structure and gene regulation. Tet enzymes remove DNA methylation [1] and their inhibition by 2HG increases DNA methylation in IDH mutant cells. 2HG also inhibits the Jumanji family of histone demethylases, increasing histone methylation.…”

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confidence: 99%

“…2HG also inhibits the Jumanji family of histone demethylases, increasing histone methylation. These and other effects of 2HG [1] perturb gene expression in IDH mutant cells and contribute to tumor formation [1].…”

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confidence: 99%

“…Mechanistically, 5-azacytidine reduces DNA methylation by inhibiting the methyl transferase DNMT1, but has additional effects on chromatin and gene regulation [8]. To further test the hypothesis that increased Clinically, high levels of 2HG may sensitise IDH-mutant tumour cells to other therapeutic approaches [1]. Alternatively, pharmacological inhibition of IDH, or selective inhibition of the abnormal enzymatic activity could be used to specifically target tumour cells [1].…”

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confidence: 99%

“…To further test the hypothesis that increased Clinically, high levels of 2HG may sensitise IDH-mutant tumour cells to other therapeutic approaches [1]. Alternatively, pharmacological inhibition of IDH, or selective inhibition of the abnormal enzymatic activity could be used to specifically target tumour cells [1]. IDH inhibitors can revert the impact of IDH mutations on chromatin state [6].…”

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confidence: 99%

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Oncometabolite Tinkers with Genome Folding, Boosting Oncogene Expression

Ing-Simmons

Merkenschlager

2016

Trends in Molecular Medicine

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confidence: 99%

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Oncometabolite Tinkers with Genome Folding, Boosting Oncogene Expression

Ing-Simmons

Merkenschlager

2016

Trends in Molecular Medicine

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“…Gain-of-function mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) lead to the inappropriate production and accumulation of R-2HG, which is thought to contribute to tumorigenesis in several tissues by altering epigenetic state and metabolism. 2 The discovery of these mutations has led to a concerted effort to understand the tumorigenic mechanisms underlying R-2HG accumulation. However, little is known about the physiological roles of R-2HG or S-2HG.…”

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confidence: 99%

S-2HG is an immunometabolite that shapes the T-cell response

Cairns

Mak

2016

Cell Death Differ

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The field of immunometabolism has expanded rapidly over the past several years, and it is now clear that specific alterations to the metabolism of immune cells occur in response to endogenous and exogenous stimuli in order to tailor the biochemistry of cells to their functional requirements and microenvironmental context. 1 Major findings in T cells have shown that, upon activation, a metabolic response is engaged, resulting in a dramatic increase in glycolysis to support rapid proliferation. Subsequently, during the formation of memory T cells, metabolism shifts away from glycolysis and back towards oxidative phosphorylation fueled by fatty acid oxidation. The mechanisms responsible for this change overlap significantly with the adaptive response to changes in oxygen concentration, but the details are not completely understood.The two chiral forms of the metabolite 2-hydroxyglutarate, R-2HG and S-2HG, are produced in mammalian cells, and are usually maintained at low levels in cells and body fluids via the activity of dedicated dehydrogenase enzymes that convert these compounds to ɑ-ketoglutarate (ɑ-KG). Gain-of-function mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) lead to the inappropriate production and accumulation of R-2HG, which is thought to contribute to tumorigenesis in several tissues by altering epigenetic state and metabolism. 2 The discovery of these mutations has led to a concerted effort to understand the tumorigenic mechanisms underlying R-2HG accumulation. However, little is known about the physiological roles of R-2HG or S-2HG. The ability of these molecules to inhibit a broad class of 2-oxoglutarate-dependent dioxygenases, including key epigenetic regulatory enzymes, suggests that they may have roles in altering the function and fate of specific cells.It has been shown previously that S-2HG increases upon exposure of cells to hypoxia or in situations where mitochondria are dysfunctional. [3][4][5] Under these conditions, S-2HG can be produced by malate dehydrogenase (MDH), lactate dehydrogenase A (LDHA), and even wild-type IDH in certain cell types. These previous studies suggest that accumulation of S-2HG plays a role in the process of hypoxic adaptation by causing epigenetic alterations that are necessary for appropriate reprogramming of metabolism. Interestingly, these previous reports found only a minor role for the HIF transcription factor, often considered the master regulator of the hypoxic response, in mediating the observed increases in S-2HG.In the current issue of Nature, Tyrakis et al. 6 report on the physiological role of S-2HG in T cells. T cells display a high degree of metabolic flexibility as their needs change during periods of rapid proliferation and cytolytic activity, and these metabolic changes are required for T-cell function and the formation of durable memory cell populations. In addition, these cells operate in a diverse array of microenvironmental conditions, including the hypoxic regions of solid tumors, healing wounds, and inflamed tissue, placing ...

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Evaluation of two new highly multiplexed PCR assays as an alternative to next‐generation sequencing for IDH1/2 mutation detection

et al. 2022

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IDH1 and IDH2 somatic mutations have been identified in solid tumors and blood malignancies. The development of inhibitors of mutant IDH1 and IDH2 in the past few years has prompted the development of a fast and sensitive assay to detect IDH1 R132 , IDH2 R140 and IDH2 R172 mutations to identify patients eligible for these targeted therapies. This study aimed to compare two new multiplexed PCR assaysan automated quantitative PCR (qPCR) on the PGX platform and a droplet digital PCR (ddPCR) with next-generation sequencing (NGS) for IDH1/2 mutation detection. These assays were evaluated on 102 DNA extracted from patient peripheral blood, bone marrow and formalin-fixed paraffin-embedded tissue samples with mutation allelic frequency ranging from 0.6% to 45.6%. The ddPCR assay had better analytical performances than the PGX assay with 100% specificity, 100% sensitivity and a detection limit down to 0.5% on IDH1 R132 , IDH2 R140 and IDH2 R172 codons, and a high correlation with NGS results. Therefore, the new highly multiplexed ddPCR is a fast and cost-effective assay that meets most clinical needs to identify and follow cancer patients in the era of anti-IDH1/2-targeted therapies.

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Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities

Cited by 378 publications

References 76 publications

Oncometabolite Tinkers with Genome Folding, Boosting Oncogene Expression

Oncometabolite Tinkers with Genome Folding, Boosting Oncogene Expression

S-2HG is an immunometabolite that shapes the T-cell response

Evaluation of two new highly multiplexed PCR assays as an alternative to next‐generation sequencing for IDH1/2 mutation detection

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