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
Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., & Kinzler, K. W. (2013) · Science · doi:10.1126/science.1235122 · Cited by 7,863
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926
Self-citationRegulation of cancer cell metabolism
Cairns, R. A., Harris, I. S., & Mak, T. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2981 · Cited by 4,744
Modulation of oxidative stress as an anticancer strategy
Gorrini, C., Harris, I. S., & Mak, T. W. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4002 · Cited by 3,579
Otto Warburg's contributions to current concepts of cancer metabolism
Koppenol, W. H., Bounds, P. L., & Dang, C. V. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3038 · Cited by 3,427
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233
Self-citationAerobic glycolysis: Meeting the metabolic requirements of cell proliferation
Lunt, S. Y., & Vander Heiden, M. G. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154237 · Cited by 3,057
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875
Mitochondrial TCA cycle metabolites control physiology and disease
Martínez-Reyes, I., & Chandel, N. S. (2020) · Nature Communications · doi:10.1038/s41467-019-13668-3 · Cited by 2,813
Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766
Self-citationDriver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
Schwartzentruber, J., Korshunov, A., Liu, X.-Y., Jones, D. T. W., Pfaff, E., Jacob, K., Sturm, D., Fontebasso, A. M., Quang, D.-A. K., Tönjes, M., et al. (2012) · Nature · doi:10.1038/nature10833 · Cited by 2,631
Metabolomics: the apogee of the omics trilogy
Patti, G. J., Yanes, Ó., & Siuzdak, G. E. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3314 · Cited by 2,605
Wallace, D. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3365 · Cited by 2,404
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380
Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma
Noushmehr, H., Weisenberger, D. J., Diefes, K., Phillips, H. S., Pujara, K., Berman, B. P., Pan, F., Pelloski, C. E., Sulman, E. P., Bhat, K. P., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.03.017 · Cited by 2,337
Understanding the Intersections between Metabolism and Cancer Biology
Heiden, M. G. V., & DeBerardinis, R. J. (2017) · Cell · doi:10.1016/j.cell.2016.12.039 · Cited by 2,369
One-Carbon Metabolism in Health and Disease
Ducker, G. S., & Rabinowitz, J. D. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.009 · Cited by 2,239
Self-citationWard, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.020 · Cited by 2,020
Self-citationPredicting the functional impact of protein mutations: application to cancer genomics
Reva, B. A., Antipin, Y., & Sander, C. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr407 · Cited by 2,046
IDH mutation impairs histone demethylation and results in a block to cell differentiation
Lu, C., Ward, P. S., Kapoor, G. S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C. R., Khanin, R., Figueroa, M. E., Melnick, A., et al. (2012) · Nature · doi:10.1038/nature10860 · Cited by 1,985
Self-citationIDH1 mutation is sufficient to establish the glioma hypermethylator phenotype
Turcan, S., Rohle, D., Goenka, A., Walsh, L. A., Fang, F., Yilmaz, E., Campos, C., Fabius, A. W. M., Lu, C., Ward, P. S., et al. (2012) · Nature · doi:10.1038/nature10866 · Cited by 1,974
Self-citationCancer metabolism: looking forward
Martínez‐Reyes, I., & Chandel, N. S. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00378-6 · Cited by 1,877
Sturm, D., Witt, H., Hovestadt, V., Khuong-Quang, D.-A., Jones, D. T. W., Konermann, C., Pfaff, E., Tönjes, M., Sill, M., Bender, S., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.08.024 · Cited by 1,828
Vyas, S., Zaganjor, E., & Haigis, M. C. (2016) · Cell · doi:10.1016/j.cell.2016.07.002 · Cited by 1,735
Serine, glycine and one-carbon units: cancer metabolism in full circle
Locasale, J. W. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3557 · Cited by 1,727
The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers
Sondka, Z., Bamford, S., Cole, C. G., Ward, S. A., Dunham, I., & Forbes, S. A. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0060-1 · Cited by 1,597
Cancer metabolism: a therapeutic perspective
Martinez-Outschoorn, U. E., Peiris-Pagés, M., Pestell, R. G., Sotgia, F., & Lisanti, M. P. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.60 · Cited by 1,505
Durable Remissions with Ivosidenib in IDH1 -Mutated Relapsed or Refractory AML
Dinardo, C. D., Stein, E. M., de Botton, S., Roboz, G. J., Altman, J. K., Mims, A. S., Swords, R. T., Collins, R. H., Mannis, G. N., Pollyea, D. A., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1716984 · Cited by 1,507
Self-citationMetabolic pathways promoting cancer cell survival and growth
Boroughs, L. K., & DeBerardinis, R. J. (2015) · Nature Cell Biology · doi:10.1038/ncb3124 · Cited by 1,499
Targeting cancer metabolism: a therapeutic window opens
Heiden, M. G. V. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3504 · Cited by 1,443
Epidemiologic and Molecular Prognostic Review of Glioblastoma
Thakkar, J. P., Dolecek, T. A., Horbinski, C., Ostrom, Q. T., Lightner, D. D., Barnholtz‐Sloan, J. S., & Villano, J. L. (2014) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-14-0275 · Cited by 1,473
Exciting New Advances in Neuro-Oncology: The Avenue to a Cure for Malignant Glioma
Van Meir, E. G., Hadjipanayis, C. G., Norden, A. D., Shu, H. K., Wen, P. Y., & Olson, J. J. (2010) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.20069 · Cited by 1,372
Fueling Immunity: Insights into Metabolism and Lymphocyte Function
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363
Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation
Moran-Crusio, K., Reavie, L., Shih, A., Abdel-Wahab, O., Ndiaye-Lobry, D., Lobry, C., Figueroa, M. E., Vasanthakumar, A., Patel, J., Zhao, X., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.06.001 · Cited by 1,339
Lessons from the Cancer Genome
Garraway, L. A., & Lander, E. S. (2013) · Cell · doi:10.1016/j.cell.2013.03.002 · Cited by 1,377
Mitochondrial metabolism and cancer
Porporato, P. E., Filigheddu, N., Pedro, J. M. B., Kroemer, G., & Galluzzi, L. (2017) · Cell Research · doi:10.1038/cr.2017.155 · Cited by 1,323
Insulator dysfunction and oncogene activation in IDH mutant gliomas
Flavahan, W. A., Drier, Y., Liau, B. B., Gillespie, S. M., Venteicher, A. S., Stemmer-Rachamimov, A. O., Suvà, M. L., & Bernstein, B. E. (2016) · Nature · doi:10.1038/nature16490 · Cited by 1,288
Zong, W., Rabinowitz, J. D., & White, E. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.011 · Cited by 1,330
Self-citationMetabolomics for Investigating Physiological and Pathophysiological Processes
Wishart, D. S. (2019) · Physiological Reviews · doi:10.1152/physrev.00035.2018 · Cited by 1,295
The Control of the Metabolic Switch in Cancers by Oncogenes and Tumor Suppressor Genes
Levine, A. J., & Puzio-Kuter, A. M. (2010) · Science · doi:10.1126/science.1193494 · Cited by 1,243
Primary brain tumours in adults
Ricard, D., Idbaïh, A., Ducray, F., Lahutte, M., Hoang‐Xuan, K., & Delattre, J. (2012) · The Lancet · doi:10.1016/s0140-6736(11)61346-9 · Cited by 1,232
Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., et al. (2012) · Genes & Development · doi:10.1101/gad.191056.112 · Cited by 1,188
An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells
Rohle, D., Popovici-Muller, J., Palaskas, N., Turcan, S., Grommes, C., Campos, C., Tsoi, J., Clark, O., Oldrini, B., Komisopoulou, E., et al. (2013) · Science · doi:10.1126/science.1236062 · Cited by 1,153
Self-citationAbou‐Alfa, G. K., Macarulla, T. M., Javle, M. M., Kelley, R. K., Lubner, S. J., Adeva, J., Cleary, J. M., Catenacci, D. V. T., Borad, M. J., Bridgewater, J. A., et al. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(20)30157-1 · Cited by 1,159
R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling
Su, R., Dong, L., Li, C., Nachtergaele, S., Wunderlich, M., Qing, Y., Deng, X., Wang, Y., Weng, X., Hu, C., et al. (2018) · Cell · doi:10.1016/j.cell.2017.11.031 · Cited by 1,137
The Definition of Primary and Secondary Glioblastoma
Ohgaki, H., & Kleihues, P. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3002 · Cited by 1,209
Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
Locasale, J. W., Grassian, A. R., Melman, T., Lyssiotis, C. A., Mattaini, K. R., Bass, A. J., Heffron, G., Metallo, C. M., Muranen, T., Sharfi, H., et al. (2011) · Nature Genetics · doi:10.1038/ng.890 · Cited by 1,120
Self-citationGlucose-Independent Glutamine Metabolism via TCA Cycling for Proliferation and Survival in B Cells
Le, A., Lane, A. N., Hamaker, M., Bose, S., Gouw, A., Barbi, J., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Zhang, H., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2011.12.009 · Cited by 1,095
Valle, J. W., Kelley, R. K., Nervi, B., Oh, D., & Zhu, A. X. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00153-7 · Cited by 1,088
Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions
Wu, H., & Zhang, Y. (2014) · Cell · doi:10.1016/j.cell.2013.12.019 · Cited by 1,065
The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases
Chowdhury, R., Yeoh, K. K., Tian, Y., Hillringhaus, L., Bagg, E. A., Rose, N. R., Leung, I. K. H., Li, X. S., Woon, E. C. Y., Yang, M., et al. (2011) · The EMBO Reports · doi:10.1038/embor.2011.43 · Cited by 1,035
Amary, M. F., Bacsi, K., Maggiani, F., Damato, S., Halai, D., Berisha, F., Pollock, R., O'Donnell, P., Grigoriadis, A., Diss, T., et al. (2011) · The Journal of Pathology · doi:10.1002/path.2913 · Cited by 1,023
Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021
Links between metabolism and cancerPreprint
Dang, C. V. (2012) · Genes & Development · doi:10.1101/gad.189365.112 · Cited by 1,021
Wise, D. R., Ward, P. S., Shay, J. E. S., Cross, J. R., Gruber, J. J., Sachdeva, U. M., Platt, J. M., DeMatteo, R. G., Simon, M. C., & Thompson, C. B. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117773108 · Cited by 975
Self-citationTargeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971
Cancer Cell Metabolism: One Hallmark, Many Faces
Cantor, J. R., & Sabatini, D. M. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0345 · Cited by 989
How cancer metabolism is tuned for proliferation and vulnerable to disruption
Schulze, A., & Harris, A. L. (2012) · Nature · doi:10.1038/nature11706 · Cited by 945
Influence of Metabolism on Epigenetics and Disease
Kaelin, W. G., & McKnight, S. L. (2013) · Cell · doi:10.1016/j.cell.2013.03.004 · Cited by 920
Cancer Epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance
Easwaran, H., Tsai, H.-C., & Baylin, S. B. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.015 · Cited by 915
Glutaminolysis: A Hallmark of Cancer Metabolism
Yang, L., Venneti, S., & Nagrath, D. (2017) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071516-044546 · Cited by 859
Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?
DeBerardinis, R. J., & Thompson, C. B. (2012) · Cell · doi:10.1016/j.cell.2012.02.032 · Cited by 858
Self-citation2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas
Choi, C., Ganji, S. K., DeBerardinis, R. J., Hatanpaa, K. J., Rakheja, D., Kovacs, Z., Yang, X.-L., Mashimo, T., Raisanen, J. M., Marin-Valencia, I., et al. (2012) · Nature Medicine · doi:10.1038/nm.2682 · Cited by 839
Metabolomics and Isotope Tracing
Jang, C., Chen, L., & Rabinowitz, J. D. (2018) · Cell · doi:10.1016/j.cell.2018.03.055 · Cited by 841
Self-citationHartmann, C. J., Hentschel, B., Wick, W., Capper, D., Felsberg, J., Simon, M., Westphal, M., Schackert, G., Meyermann, R., Pietsch, T., et al. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0781-z · Cited by 823
Yan, X., Xu, J., Gu, Z., Pan, C., Lü, G., Shen, Y., Shi, J., Zhu, Y., Tang, L., Zhang, X., et al. (2011) · Nature Genetics · doi:10.1038/ng.788 · Cited by 837
Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation
Wang, F., Travins, J., DeLaBarre, B., Penard-Lacronique, V., Schalm, S., Hansen, E., Straley, K., Kernytsky, A., Liu, W., Gliser, C., et al. (2013) · Science · doi:10.1126/science.1234769 · Cited by 804
Self-citationPaschka, P., Schlenk, R. F., Gaidzik, V. I., Habdank, M., Krönke, J., Bullinger, L., Späth, D., Käyser, S., Zucknick, M., Götze, K. S. S., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.3762 · Cited by 820
Metabolic reprogramming and epigenetic modifications on the path to cancer
Sun, L., Zhang, H., & Gao, P. (2021) · Protein & Cell · doi:10.1007/s13238-021-00846-7 · Cited by 818
Wolf, A., Agnihotri, S., Micallef, J., Mukherjee, J., Sabha, N., Cairns, R., Hawkins, C., & Guha, A. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20101470 · Cited by 789
Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma
Huse, J. T., & Holland, E. C. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2818 · Cited by 783
Marcucci, G., Maharry, K. S., Wu, Y.-Z., Radmacher, M. D., Mrózek, K., Margeson, D., Holland, K. B., Whitman, S. P., Becker, H., Schwind, S., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.3730 · Cited by 785
Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy
Shao, H., Chung, J., Balaj, L., Charest, A., Bigner, D. D., Carter, B. S., Hochberg, F. H., Breakefield, X. O., Weissleder, R., & Lee, H. (2012) · Nature Medicine · doi:10.1038/nm.2994 · Cited by 782
Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation
Xie, Z., Zhang, D., Chung, D., Tang, Z., Huang, H., Dai, L., Qi, S., Li, J., Colak, G., Chen, Y., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.03.036 · Cited by 744
Gross, S., Cairns, R. A., Minden, M. D., Driggers, E. M., Bittinger, M. A., Jang, H. G., Sasaki, M., Jin, S., Schenkein, D. P., Su, S. M., et al. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20092506 · Cited by 736
Self-citationBorger, D. R., Tanabe, K. K., Fan, K. C., Lopez, H. U., Fantin, V. R., Straley, K. S., Schenkein, D. P., Hezel, A. F., Ancukiewicz, M., Liebman, H. M., et al. (2012) · The Oncologist · doi:10.1634/theoncologist.2011-0386 · Cited by 728
Self-citationTransformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation
Koivunen, P., Lee, S., Duncan, C. G., Lopez, G., Lu, G., Ramkissoon, S., Losman, J. A., Joensuu, P., Bergmann, U., Gross, S., et al. (2012) · Nature · doi:10.1038/nature10898 · Cited by 727
Metabolic Modulation of Glioblastoma with Dichloroacetate
Michelakis, E. D., Sutendra, G., Dromparis, P., Webster, L., Haromy, A., Niven, E. B., Maguire, C., Gammer, T.-L., Mackey, J. R., Fulton, D. S., et al. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3000677 · Cited by 744
Metabolomics: an emerging but powerful tool for precision medicinePreprint
Clish, C. B. (2015) · Molecular Case Studies · doi:10.1101/mcs.a000588 · Cited by 769
A vaccine targeting mutant IDH1 induces antitumour immunity
Schumacher, T., Bunse, L., Pusch, S., Sahm, F., Wiestler, B., Quandt, J., Menn, O., Osswald, M., Oezen, I., Ott, M., et al. (2014) · Nature · doi:10.1038/nature13387 · Cited by 727
Metabolic targets for cancer therapy
Galluzzi, L., Kepp, O., Heiden, M. G. V., & Kroemer, G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4145 · Cited by 731
( R )-2-Hydroxyglutarate Is Sufficient to Promote Leukemogenesis and Its Effects Are Reversible
Losman, J.-A., Looper, R. E., Koivunen, P., Lee, S., Schneider, R. K., McMahon, C., Cowley, G. S., Root, D. E., Ebert, B. L., & Kaelin, W. G. (2013) · Science · doi:10.1126/science.1231677 · Cited by 703
Metabolic Regulation of Epigenetics
Lu, C., & Thompson, C. B. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.06.001 · Cited by 699
Self-citationKurhanewicz, J., Vigneron, D. B., Brindle, K., Chekmenev, E. Y., Comment, A., Cunningham, C. H., DeBerardinis, R. J., Green, G. G., Leach, M. O., Rajan, S. S., et al. (2011) · Neoplasia · doi:10.1593/neo.101102 · Cited by 681
Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism
Yi, W., Clark, P. M., Mason, D. E., Keenan, M. C., Hill, C., Goddard, W. A., Peters, E. C., Driggers, E. M., & Hsieh‐Wilson, L. C. (2012) · Science · doi:10.1126/science.1222278 · Cited by 696
Self-citationThe genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia
Sperling, A. S., Gibson, C. J., & Ebert, B. L. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.112 · Cited by 706
The role of mutations in epigenetic regulators in myeloid malignancies
Shih, A. H., Abdel-Wahab, O. I., Patel, J. P., & Levine, R. L. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3343 · Cited by 696
Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidationPreprint
Wu, H., & Zhang, Y. (2011) · Genes & Development · doi:10.17615/800j-yk16 · Cited by 686
IDH mutation in glioma: molecular mechanisms and potential therapeutic targets
Han, S., Liu, Y., Cai, S. J., Qian, M., Ding, J., Larion, M., Gilbert, M. R., & Yang, C. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0814-x · Cited by 701
Zhang, W. C., Shyh-Chang, N., Yang, H., Rai, A., Umashankar, S., Ma, S., Soh, B. S., Sun, L. L., Tai, B. C., Nga, M. E., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.050 · Cited by 660
Seyfried, T. N., & Shelton, L. M. (2010) · Nutrition & Metabolism · doi:10.1186/1743-7075-7-7 · Cited by 675
Metabolomics in cancer research and emerging applications in clinical oncology
Schmidt, D. R., Patel, R., Kirsch, D. G., Lewis, C. A., Heiden, M. G. V., & Locasale, J. W. (2021) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21670 · Cited by 675
Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine
Zhang, J., Pavlova, N. N., & Thompson, C. B. (2017) · The EMBO Journal · doi:10.15252/embj.201696151 · Cited by 651
Self-citationTranscription factors as readers and effectors of DNA methylation
Zhu, H., Wang, G., & Qian, J. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.83 · Cited by 649
IDH1 and IDH2 mutations in gliomas
Cohen, A. L., Holmen, S. L., & Colman, H. (2013) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-013-0345-4 · Cited by 629
Khwaja, A., Björkholm, M., Gale, R. E., Levine, R. L., Jordan, C. T., Ehninger, G., Bloomfield, C. D., Estey, E. H., Burnett, A. K., Cornelissen, J. J., et al. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.10 · Cited by 636
Mechanisms and Implications of Metabolic Heterogeneity in Cancer
Kim, J., & DeBerardinis, R. J. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.08.013 · Cited by 606
Metabolomic Analysis and Visualization Engine for LC−MS Data
Melamud, E., Vastag, L., & Rabinowitz, J. D. (2010) · Analytical Chemistry · doi:10.1021/ac1021166 · Cited by 615
Self-citationThe Mitochondrial Proteome and Human Disease
Calvo, S. E., & Mootha, V. K. (2010) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-082509-141720 · Cited by 590
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
