The DOI matches its Crossref record; 26 of the 26 references it cites were found in a registry or an index.
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Open accessAbstract
Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7.”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [3]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7.”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [3]
In the citing paper
“Wild-type IDH1 and IDH2 catalyze the reversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate (αKG) and CO2 (Figure 4a). Cancer associated mutations in IDH1 and IDH2 eliminate this function and confer a neomorphic activity to the enzyme, generating D-2-hydroxyglutarate (D-2HG) via the reduction of αKG (Figure 4b)(Dang et al., 2009; Ward et al., 2010).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Dang et al., 2009
In the citing paper
“cancer-associated IDH1 R132 mutants display a loss-of-function for the use of isocitrate as substrate, with a concomitant gain-of-function for the reduction of α-ketoglutarate to 2HG”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Dang et al., 2009
In the citing paper
“There is a marked difference in the enzymatic rate of isocitrate-dependent NADPH production by the wild-type proteins and α-ketoglutarate-dependent NADPH consumption by both IDH1 and IDH2 mutants (Figure 2 and Dang et al., 2009).”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Dang et al., 2009
In the citing paper
“2HG was found to be elevated in IDH1-mutated gliomas”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Dang et al., 2009
In the citing paper
“The R132H IDH1 mutation observed in gliomas was found to display a gain of function for the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG)”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Dang et al., 2009
In the citing paper
“In the case of IDH1 mutant proteins, it has been reported that a local supply of NADPH and α-ketoglutarate is required to drive 2HG production (Dang et al., 2009).”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Dang et al., 2009
In the citing paper
“Thus, various tumors, including glioma, secondary glioblastoma, and acute myeloid leukemia (AML), harboring heterozygous point mutations in the active sites of IDH1/2 show dramatic increases in the R-2-HG levels111,113–115.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [111]
In the citing paper
“Although additional studies are needed, ample experimental data support the recognition of R-2-HG, succinate, and fumarate as oncometabolites.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [111]
In the citing paper
“These results suggest that 2HG-and in particular the R-enantiomer produced by IDH1 mutants (Dang et al, 2009)-is probably an ineffective inhibitor of HIF Pro-hydroxylation, and predict that it would be relatively ineffective in inducing HIF1a.”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Dang et al, 2009
In the citing paper
“The high concentrations of R-2HG (more than 10 mM) that have been observed in malignant brain tumours and leukaemias (Dang et al, 2009;Gross et al, 2010;Ward et al, 2010), might be sufficient to inhibit even the less-susceptible 2OG oxygenases.”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Dang et al, 2009
In the citing paper
“As production of 2HG by IDH mutations is stereospecific (Dang et al, 2009;Ward et al, 2010), the specificity of inhibition by the 2HG enantiomers is relevant to their potential as mediators of oncogenic pathways.”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Dang et al, 2009
In the citing paper
“However, they also cause a gain of function comprising catalysis of 2OG to the R-enantiomer of 2-hydroxyglutarate (R-2HG; Dang et al, 2009;Gross et al, 2010;Ward et al, 2010).”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Dang et al, 2009
In the citing paper
“Tumor-associated IDH mutations unmask a latent ability of these enzymes to produce the R enantiomer of 2-hydroxyglutarate, which accumulates to low millimolar levels in IDH mutant tumors (Dang et al., 2009; Gross et al., 2010; Ward et al., 2010).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Dang et al., 2009
In the citing paper
“Mutant IDH protein is a competitive inhibitor of hydroxylases, including the TET family of 5mC hydroxylases120–122.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [121]
In the citing paper
“Oncogenic mutations in genes encoding IDH1/2 result in neomorphic enzyme activity that favors reduction of αKG to d-2-hydroxyglutarate (D-2HG) (167, 168).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [167]
In the citing paper
“This mutation alters the enzymatic ability of IDH1, allowing it to convert α-KG to 2-hydroxyglutarate (2-HG) rather than promote normal isocitrate–to–α-KG inter-conversion (78).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [78]
In the citing paper
“The weight of the evidence now suggests that regulation of HIF-1 stability through decreased PHD2 activity is not the primary effect of IDH mutations (Chowdhury et al., 2011; Dang et al., 2009; Jin et al., 2011; Mardis et al., 2009; Metellus et al., 2011; Williams et al., 2011).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Dang et al., 2009
In the citing paper
“IDH1 mutations at R132 are not simply loss-of-function for isocitrate and α-ketoglutarate interconversion, but also acquire a novel reductive activity to convert α-ketoglutarate to 2-hydroxyglutarate (2HG)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Dang et al., 2009
In the citing paper
“a rare metabolite found at only trace amounts in mammalian cells under normal conditions (Dang et al., 2009)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Dang et al., 2009
In the citing paper
“R(-)-2HG (also known as D-2HG) is the exclusive 2HG stereoisomer produced by IDH1 and IDH2 mutants (Dang et al., 2009; Ward et al., 2010)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Dang et al., 2009
In the citing paper
“This suspicion was confirmed by metabolomics: tumor tissue and cell lines expressing mutant IDH1 or IDH2 produced large quantities of a metabolite, (D)-2-hydroxyglutarate (2-HG), that is vanishingly scarce when only the wild-type enzymes were expressed (Dang et al., 2009).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Dang et al., 2009
In the citing paper
“Surprisingly, even large accumulations of 2-HG do not cause wholesale perturbations of metabolite levels in IDH1-mutant tumors (Dang et al., 2009).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Dang et al., 2009
In the citing paper
“These findings therefore suggest that both suppression of RIP3-mediated necroptosis and MLK3-mediated apoptosis by D-2-HG may contribute to IDH-mutant carcinogenesis140,141.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [141]
In the citing paper
“Finally, D-2HG also impairs necroptosis and the small GTPase Cdc42, leading to suppression of mixed lineage kinase 3 (MLK3)-mediated apoptosis140,141.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [141]
In the citing paper
“D-2-HG has also been found to bind the DNA methyltransferase DNMT1, which subsequently represses receptor-interacting protein kinase 3 (RIP3).”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [141]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612
The PyMOL Molecular Graphics System
DeLano, W. L. (2002) · Medical Entomology and Zoology · Cited by 18,147
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,317
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
IDH1 and IDH2 Mutations in Gliomas
Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808710 · Cited by 5,847
Recurring mutations found by sequencing an acute myeloid leukemia genome
Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0903840 · Cited by 2,219
Hartmann, C. J., Meyer, J., Balß, J., Capper, D., Mueller, W. C., Christians, A., Felsberg, J., Wolter, M., Mawrin, C., Wick, W., et al. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0561-9 · Cited by 1,163
Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α
Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., et al. (2009) · Science · doi:10.1126/science.1170944 · Cited by 1,119
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–200 of 1,009
MGMT testing—the challenges for biomarker-based glioma treatment
Wick, W., Weller, M., van den Bent, M. J., Sanson, M., Weiler, M., von Deimling, A., Plass, C., Hegi, M. E., Platten, M., & Reifenberger, G. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.100 · Cited by 599
Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia
Chan, S. M., Thomas, D., Corces, M. R., Xavy, S., Rastogi, S., Hong, W., Zhao, F., Medeiros, B. C., Tyvoll, D. A., & Majeti, R. (2015) · Nature Medicine · doi:10.1038/nm.3788 · Cited by 597
Yang, H., Liu, Y., Bai, F., Zhang, J., Ma, S.-H., Liu, J., Xu, Z.-D., Zhu, H.-G., Ling, Z.-Q., Ye, D., et al. (2012) · Oncogene · doi:10.1038/onc.2012.67 · Cited by 581
What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer
Losman, J.-A., & Kaelin, W. G. (2013) · Genes & Development · doi:10.1101/gad.217406.113 · Cited by 570
Regulation of the pentose phosphate pathway in cancer
Jiang, P., Du, W., & Wu, M. (2014) · Protein & Cell · doi:10.1007/s13238-014-0082-8 · Cited by 587
Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells
Lewis, C. A., Parker, S. J., Fiske, B. P., McCloskey, D., Gui, D. Y., Green, C. R., Vokes, N. I., Feist, A. M., Vander Heiden, M. G., & Metallo, C. M. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.008 · Cited by 562
Reitman, Z. J., & Yan, H. (2010) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djq187 · Cited by 562
Pansuriya, T. C., van Eijk, R., d'Adamo, P., van Ruler, M. A. J. H., Kuijjer, M. L., Oosting, J., Cleton-Jansen, A.-M., van Oosterwijk, J. G., Verbeke, S. L. J., Meijer, D., et al. (2011) · Nature Genetics · doi:10.1038/ng.1004 · Cited by 559
Emerging insights into the molecular and cellular basis of glioblastomaPreprint
Dunn, G. P., Rinne, M. L., Wykosky, J., Genovese, G., Quayle, S. N., Dunn, I. F., Agarwalla, P. K., Chheda, M. G., Campos, B., Wang, A., et al. (2012) · Genes & Development · doi:10.1101/gad.187922.112 · Cited by 573
The emerging role and targetability of the TCA cycle in cancer metabolism
Anderson, N. M., Mucka, P., Kern, J. G., & Feng, H. (2017) · Protein & Cell · doi:10.1007/s13238-017-0451-1 · Cited by 586
Sulkowski, P. L., Corso, C. D., Robinson, N. D., Scanlon, S. E., Purshouse, K. R., Bai, H., Liu, Y., Sundaram, R. K., Hegan, D. C., Fons, N. R., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aal2463 · Cited by 575
Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge
Sturm, D., Bender, S., Jones, D. T. W., Lichter, P., Grill, J., Becher, O., Hawkins, C., Majewski, J., Jones, C., Costello, J. F., et al. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3655 · Cited by 555
Metabolic Regulation of T Cell Longevity and Function in Tumor Immunotherapy
Kishton, R. J., Sukumar, M., & Restifo, N. P. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.016 · Cited by 548
The roles of DNA, RNA and histone methylation in ageing and cancer
Michalak, E. M., Burr, M. L., Bannister, A. J., & Dawson, M. A. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0143-1 · Cited by 549
Glioma epigenetics: From subclassification to novel treatment options
Gusyatiner, O., & Hegi, M. E. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.11.010 · Cited by 556
Mutations in CIC and FUBP1 Contribute to Human Oligodendroglioma
Bettegowda, C., Agrawal, N., Jiao, Y., Sausen, M., Wood, L. D., Hruban, R. H., Rodríguez, F. J., Cahill, D. P., McLendon, R. E., Riggins, G. J., et al. (2011) · Science · doi:10.1126/science.1210557 · Cited by 561
Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
Bunse, L., Pusch, S., Bunse, T., Sahm, F., Sanghvi, K., Friedrich, M., Alansary, D., Sonner, J. K., Green, E., Deumelandt, K., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0095-6 · Cited by 566
Ivosidenib and Azacitidine in IDH1 -Mutated Acute Myeloid Leukemia
Montesinos, P., Récher, C., Vives, S., Zarzycka, E., Wang, J., Bertani, G., Heuser, M., Calado, R. T., Schuh, A. C., Yeh, S., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2117344 · Cited by 568
Regulation and function of the mammalian tricarboxylic acid cycle
Arnold, P. K., & Finley, L. W. S. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102838 · Cited by 535
Tefferi, A. (2010) · Leukemia · doi:10.1038/leu.2010.69 · Cited by 544
Malignant Glioma: Lessons from Genomics, Mouse Models, and Stem Cells
Chen, J., McKay, R. M., & Parada, L. F. (2012) · Cell · doi:10.1016/j.cell.2012.03.009 · Cited by 549
Interplay between Metabolism and Epigenetics: A Nuclear Adaptation to Environmental Changes
Etchegaray, J., & Mostoslavsky, R. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.05.029 · Cited by 546
Choosing between glycolysis and oxidative phosphorylation: a tumor’s dilemma?
Jose, C., Bellance, N., & Rossignol, R. (2011) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.10.012 · Cited by 518
The impact of cellular metabolism on chromatin dynamics and epigenetics
Reid, M. A., Dai, Z., & Locasale, J. W. (2017) · Nature Cell Biology · doi:10.1038/ncb3629 · Cited by 515
IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics
Sasaki, M., Knobbe, C. B., Munger, J. C., Lind, E. F., Brenner, D., Brüstle, A., Harris, I. S., Holmes, R., Wakeham, A., Haight, J., et al. (2012) · Nature · doi:10.1038/nature11323 · Cited by 513
Self-citationGlioblastoma: From Molecular Pathology to Targeted Treatment
Cloughesy, T. F., Cavenee, W. K., & Mischel, P. S. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130324 · Cited by 531
Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1
Seltzer, M. J., Bennett, B. D., Joshi, A. D., Gao, P., Thomas, A. G., Ferraris, D. V., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Rabinowitz, J. D., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1666 · Cited by 528
Self-citationThe landscape of cancer cell line metabolism
Li, H., Ning, S., Ghandi, M., Kryukov, G. V., Gopal, S., Deik, A., Souza, A., Pierce, K. A., Keskula, P., Hernandez, D., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0404-8 · Cited by 511
IDH mutations in cancer and progress toward development of targeted therapeutics
Dang, L., Yen, K., & Attar, E. C. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw013 · Cited by 509
Self-citationLC‐MS Data Processing with MAVEN: A Metabolomic Analysis and Visualization Engine
Clasquin, M. F., Melamud, E., & Rabinowitz, J. D. (2012) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi1411s37 · Cited by 513
Self-citationIDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma
Cairns, R. A., Iqbal, J., Lemonnier, F., Küçük, C., de Leval, L., Jaïs, J., Parrens, M., Martin, A., Xerri, L., Brousset, P., et al. (2012) · Blood · doi:10.1182/blood-2011-11-391748 · Cited by 522
Rational combinations of targeted cancer therapies: background, advances and challenges
Jin, H., Wang, L., & Bernards, R. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00615-z · Cited by 503
New aspects of amino acid metabolism in cancer
Vettore, L. A., Westbrook, R. L., & Tennant, D. A. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0620-5 · Cited by 508
The Warburg effect: 80 years on
Potter, M., Newport, E., & Morten, K. (2016) · Biochemical Society Transactions · doi:10.1042/bst20160094 · Cited by 530
Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery
Merk, A., Bartesaghi, A., Banerjee, S., Falconieri, V., Rao, P., Davis, M. I., Pragani, R., Boxer, M. B., Earl, L. A., Milne, J. L. S., et al. (2016) · Cell · doi:10.1016/j.cell.2016.05.040 · Cited by 511
Chan-on, W., Nairismägi, M., Ong, C. K., Lim, W. K., Dima, S., Pairojkul, C., Lim, K. H., McPherson, J. R., Cutcutache, I., Heng, H. L., et al. (2013) · Nature Genetics · doi:10.1038/ng.2806 · Cited by 495
Epigenetic Therapies for Cancer
Bates, S. E. (2020) · New England Journal of Medicine · doi:10.1056/nejmra1805035 · Cited by 503
Therapeutic targeting of the hypoxic tumour microenvironment
Singleton, D. C., Macann, A., & Wilson, W. R. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00539-4 · Cited by 507
Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer
Sivanand, S., & Heiden, M. G. V. (2020) · Cancer Cell · doi:10.1016/j.ccell.2019.12.011 · Cited by 498
BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1
Tönjes, M., Barbus, S., Park, Y. J., Wang, W., Schlotter, M., Lindroth, A. M., Pleier, S. V., Bai, A. H. C., Karra, D., Piro, R. M., et al. (2013) · Nature Medicine · doi:10.1038/nm.3217 · Cited by 486
Emerging patterns of somatic mutations in cancer
Watson, I. R., Takahashi, K., Futreal, P. A., & Chin, L. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3539 · Cited by 497
AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
Yen, K., Travins, J., Wang, F., David, M. D., Artin, E., Straley, K., Padyana, A., Gross, S., DeLaBarre, B., Tobin, E., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1034 · Cited by 471
Self-citationThe mutational landscape of adenoid cystic carcinoma
Ho, A. S., Kannan, K. S., Roy, D. M., Morris, L. G. T., Ganly, I., Katabi, N., Ramaswami, D., Walsh, L. A., Eng, S., Huse, J. T., et al. (2013) · Nature Genetics · doi:10.1038/ng.2643 · Cited by 472
Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer
Saha, S. K., Parachoniak, C. A., Ghanta, K. S., Fitamant, J., Ross, K. N., Najem, M. S., Gurumurthy, S., Akbay, E. A., Sia, D., Cornellà, H., et al. (2014) · Nature · doi:10.1038/nature13441 · Cited by 460
Self-citationIDH1andIDH2Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives
Yang, H., Ye, D., Guan, K., & Xiong, Y. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1773 · Cited by 477
Diffuse Glioma Heterogeneity and Its Therapeutic Implications
Nicholson, J., & Fine, H. A. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1474 · Cited by 478
Popovici-Müller, J. V., Lemieux, R. M., Artin, E., Saunders, J. O., Salituro, F. G., Travins, J. M., Cianchetta, G., Cai, Z., Zhou, D., Cui, D., et al. (2018) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.7b00421 · Cited by 457
Self-citationLiu, X., & Locasale, J. W. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.01.004 · Cited by 453
Recent advances in the molecular understanding of glioblastoma
Bleeker, F. E., Molenaar, R. J., & Leenstra, S. (2012) · Journal of Neuro-Oncology · doi:10.1007/s11060-011-0793-0 · Cited by 468
Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities
Cairns, R. A., & Mak, T. W. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0083 · Cited by 452
Challenges and Opportunities in Cancer Drug Resistance
Ward, R. A., Fawell, S. E., Floc’h, N., Flemington, V., McKerrecher, D., & Smith, P. D. (2020) · Chemical Reviews · doi:10.1021/acs.chemrev.0c00383 · Cited by 461
Tumor glycolysis, an essential sweet tooth of tumor cells
Paul, S., Ghosh, S., & Kumar, S. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.09.007 · Cited by 449
Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome
Reitman, Z. J., Jin, G., Karoly, E. D., Spasojevic, I., Yang, J., Kinzler, K. W., He, Y., Bigner, D. D., Vogelstein, B., & Yan, H. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019393108 · Cited by 449
Yu, W., Dittenhafer‐Reed, K. E., & Denu, J. M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.355206 · Cited by 452
NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink
Ulanovskaya, O. A., Zuhl, A. M., & Cravatt, B. F. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1204 · Cited by 454
Protein degradation – an alternative respiratory substrate for stressed plants
Araújo, W. L., Tohge, T., Ishizaki, K., Leaver, C. J., & Fernie, A. R. (2011) · Trends in Plant Science · doi:10.1016/j.tplants.2011.05.008 · Cited by 452
Jin, S., Jiang, Y., Qiu, R., Rauch, T. A., Wang, Y., Schackert, G., Krex, D., Lü, Q., & Pfeifer, G. P. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-2023 · Cited by 449
Self-citationAndronesi, O. C., Kim, G. S., Gerstner, E., Batchelor, T., Tzika, A. A., Fantin, V. R., Vander Heiden, M. G., & Sorensen, A. G. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3002693 · Cited by 438
Self-citationEnergy metabolism in health and diseases
Liu, H., Wang, S., Wang, J., Guo, X., Song, Y., Fu, K., Gao, Z., Liu, D., He, W., & Yang, L. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02141-x · Cited by 484
Mitochondrial dysfunction and mitochondrial dynamics-The cancer connection
Srinivasan, S., Guha, M., Kashina, A., & Avadhani, N. G. (2017) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2017.01.004 · Cited by 452
Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion
Tateishi, K., Wakimoto, H., Iafrate, A. J., Tanaka, S., Loebel, F., Lelic, N., Wiederschain, D., Bedel, O., Deng, G., Zhang, B., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.11.006 · Cited by 433
S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate
Tyrakis, P. A., Palazon, A., Macias, D., Lee, K. L., Phan, A. T., Veliça, P., You, J., Chia, G. S., Sim, J., Doedens, A., et al. (2016) · Nature · doi:10.1038/nature20165 · Cited by 433
Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2
Amary, M. F., Damato, S., Halai, D., Eskandarpour, M., Berisha, F., Bonar, F., McCarthy, S., Fantin, V. R., Straley, K. S., Lobo, S., et al. (2011) · Nature Genetics · doi:10.1038/ng.994 · Cited by 428
Self-citationMYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis
Terunuma, A., Putluri, N., Mishra, P., Mathé, E. A., Dorsey, T. H., Yi, M., Wallace, T. A., Issaq, H. J., Zhou, M., Killian, J. K., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci71180 · Cited by 428
Oncometabolites: linking altered metabolism with cancer
Yang, M. H., Soga, T., & Pollard, P. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67228 · Cited by 441
Anticancer Targets in the Glycolytic Metabolism of Tumors: A Comprehensive Review
Porporato, P. E., Dhup, S., Dadhich, R. K., Copetti, T., & Sonveaux, P. (2011) · Frontiers in Pharmacology · doi:10.3389/fphar.2011.00049 · Cited by 449
The nexus of chromatin regulation and intermediary metabolism
Gut, P., & Verdin, E. M. (2013) · Nature · doi:10.1038/nature12752 · Cited by 431
Metabolic control of epigenetics in cancer
Kinnaird, A. S., Zhao, S., Wellen, K. E., & Michelakis, E. D. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.82 · Cited by 429
Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer
Mohammad, H. P., Barbash, O., & Creasy, C. L. (2019) · Nature Medicine · doi:10.1038/s41591-019-0376-8 · Cited by 427
Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas
Kohanbash, G., Carrera, D. A., Shrivastav, S., Ahn, B. J., Jahan, N., Mazor, T., Chheda, Z. S., Downey, K., Watchmaker, P. B., Beppler, C., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90644 · Cited by 420
The importance of serine metabolism in cancer
Mattaini, K. R., Sullivan, M. R., & Heiden, M. G. V. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201604085 · Cited by 423
Heterogeneity of tumor-induced gene expression changes in the human metabolic network
Hu, J., Locasale, J. W., Bielas, J. H., O'Sullivan, J., Sheahan, K., Cantley, L. C., Heiden, M. G. V., & Vitkup, D. (2013) · Nature Biotechnology · doi:10.1038/nbt.2530 · Cited by 407
Self-citationAltered metabolite levels in cancer: implications for tumour biology and cancer therapy
Sullivan, L. B., Gui, D. Y., & Heiden, M. G. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.85 · Cited by 406
The language of chromatin modification in human cancers
Zhao, S., Allis, C. D., & Wang, G. G. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00357-x · Cited by 420
Mutant IDH1 regulates the tumor-associated immune system in gliomasPreprint
Amankulor, N., Kim, Y., Arora, S., Kargl, J., Szulzewsky, F., Hanke, M. L., Margineantu, D. H., Rao, A., Bolouri, H., Delrow, J. J., et al. (2017) · Genes & Development · doi:10.1101/gad.294991.116 · Cited by 411
The implications of IDH mutations for cancer development and therapy
Pirozzi, C. J., & Yan, H. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00521-0 · Cited by 417
Wang, P., Dong, Q., Zhang, C., Kuan, P.-F., Liu, Y., Jeck, W. R., Andersen, J. B., Jiang, W., Savich, G. L., Tan, T.-X., et al. (2013) · Oncogene · doi:10.1038/onc.2012.315 · Cited by 399
Daemen, A., Peterson, D., Sahu, N., McCord, R., Du, X., Liu, B., Kowanetz, K., Hong, R., Moffat, J., Gao, M., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1501605112 · Cited by 398
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398
Cancer cell metabolism: implications for therapeutic targets
Jang, M., Kim, S. S., & Lee, J. (2013) · Experimental & Molecular Medicine · doi:10.1038/emm.2013.85 · Cited by 405
Recurrent SETBP1 mutations in atypical chronic myeloid leukemia
Piazza, R., Valletta, S., Winkelmann, N., Redaelli, S., Spinelli, R., Pirola, A., Antolini, L., Mologni, L., Donadoni, C., Papaemmanuil, E., et al. (2012) · Nature Genetics · doi:10.1038/ng.2495 · Cited by 400
Self-citationInhibition of 2-oxoglutarate dependent oxygenases
Rose, N. R., McDonough, M. A., King, O. N. F., Kawamura, A., & Schofield, C. J. (2011) · Chemical Society Reviews · doi:10.1039/c0cs00203h · Cited by 405
The Keap1–Nrf2 system in cancers: stress response and anabolic metabolism
Mitsuishi, Y., Motohashi, H., & Yamamoto, M. P. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00200 · Cited by 411
Extracellular Metabolic Energetics Can Promote Cancer Progression
Loo, J. M., Scherl, A., Nguyen, A., Man, F. Y., Weinberg, E., Zeng, Z., Saltz, L., Paty, P. B., & Tavazoie, S. F. (2015) · Cell · doi:10.1016/j.cell.2014.12.018 · Cited by 393
Cancer Development, Progression, and Therapy: An Epigenetic Overview
Sarkar, S., Horn, G., Moulton, K. L., Oza, A. U., Byler, S., Kokolus, S., & Longacre, M. M. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms141021087 · Cited by 425
The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8
Zhang, J.-Y., Zhou, B., Sun, R.-Y., Ai, Y.-L., Cheng, K., Li, F.-N., Wang, B.-R., Liu, F.-J., Jiang, Z., Wang, W., et al. (2021) · Cell Research · doi:10.1038/s41422-021-00506-9 · Cited by 394
Trujillo, J., Sweis, R. F., Bao, R., & Luke, J. J. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0277 · Cited by 396
The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease
Johnson, A. A., Akman, K., Calimport, S., Wuttke, D., Stolzing, A., & de Magalhães, J. P. (2012) · Rejuvenation Research · doi:10.1089/rej.2012.1324 · Cited by 399
Cancer metabolism: current perspectives and future directions
Muñoz-Pinedo, C., El Mjiyad, N., & Ricci, J.-E. (2012) · Cell Death & Disease · doi:10.1038/cddis.2011.123 · Cited by 385
Roboz, G. J., Dinardo, C. D., Stein, E. M., de Botton, S., Mims, A. S., Prince, G. T., Altman, J. K., Arellano, M. L., Donnellan, W., Erba, H. P., et al. (2019) · Blood · doi:10.1182/blood.2019002140 · Cited by 397
Self-citationvan den Bent, M. J., Dubbink, H. J., Marie, Y., Brandes, A. A., TAPHOORN, M. J. B., Wesseling, P., Frénay, M., Tijssen, C. C., Lacombe, D. A., Idbaïh, A., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-2902 · Cited by 384
Gritsch, S., Batchelor, T. T., & Castro, L. N. G. (2021) · Cancer · doi:10.1002/cncr.33918 · Cited by 406
Long, G. V., Fung, C., Menzies, A. M., Pupo, G. M., Carlino, M. S., Hyman, J., Shahheydari, H., Tembe, V., Thompson, J. F., Saw, R. P., et al. (2014) · Nature Communications · doi:10.1038/ncomms6694 · Cited by 375
Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis
Daye, D., & Wellen, K. E. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.02.002 · Cited by 387
Pan, M., Reid, M. A., Lowman, X. H., Kulkarni, R. P., Tran, T. Q., Liu, X., Yang, Y., Hernandez-Davies, J. E., Rosales, K. K., Li, H., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3410 · Cited by 368
McBrayer, S. K., Mayers, J. R., DiNatale, G. J., Shi, D. D., Khanal, J., Chakraborty, A. A., Sarosiek, K. A., Briggs, K. J., Robbins, A. K., Sewastianik, T., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.038 · Cited by 368
IDH mutations in glioma and acute myeloid leukemia
Dang, L., Jin, S., & Su, S.-S. M. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.07.002 · Cited by 384
Self-citationUnderstanding metabolic regulation and its influence on cell physiology
Metallo, C. M., & Vander Heiden, M. G. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.018 · Cited by 367
The Significance of Mitochondrial Dysfunction in Cancer
Luo, Y., Ma, J., & Lu, W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165598 · Cited by 380
Oldham, W. M., Clish, C. B., Yang, Y., & Loscalzo, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.021 · Cited by 364
Metadata
- Authors
- Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., Marks, K. M., Prins, R. M., Ward, P. S., Yen, K. E., Liau, L. M., Rabinowitz, J. D., Cantley, L. C., Thompson, C. B., Vander Heiden, M. G., & Su, S. M.
- Affiliations
- Agios Pharmaceuticals (United States) (US)
- Princeton University (US)
- University of California, Los Angeles (US)
- Abramson Cancer Center (US)
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Venue
- Nature
- Published
- 2009-11-22
- Volume
- 462
- Issue
- 7274
- Pages
- 739-744
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2818760
- OpenAlex
- W2080452140
- Cited by
- 4,154
- References
- 26
- Citations by year
- 2026: 184 · 2025: 230 · 2024: 250 · 2023: 257 · 2022: 285 · 2021: 315 · 2020: 297 · 2019: 267 · 2018: 280 · 2017: 270 · 2016: 273 · 2015: 245 · 2014: 218 · 2013: 225 · 2012: 218
- FWCI
- 88.03
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-06-17)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P01CA104838, R21CA128620, R01CA105463)
- National Institute of Biomedical Imaging and Bioengineering (P30EB009998)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- IDH1 mutation, 2-hydroxyglutarate, gain-of-function mutations, isocitrate dehydrogenase, high-grade glioma, glioblastoma, oncometabolites, carcinogenesis, brain cancer, enzyme structure, tumor progression
- MeSH terms
- Arginine, Brain Neoplasms, Cell Line, Glioma, Glutarates, Histidine, Humans, Isocitrate Dehydrogenase, Ketoglutaric Acids, Models, Molecular, Mutation, Protein Conformation, Crystallography, X-Ray, Disease Progression, Catalytic Domain, Mutant Proteins, Enzyme Assays
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
