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Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations
Open accessAbstract
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel nicotinamide adenine dinucleotide phosphate (NADPH)–dependent reduction of α-ketoglutarate (α-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and α-KG. This prevents the oxidative decarboxylation of isocitrate to α-KG, and facilitates the conversion of α-KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity.
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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 Gross et al, 2010
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 Gross et al, 2010
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 Gross et al., 2010
In the citing paper
“AML samples with low to undetectable 2HG were subsequently sequenced and determined to be IDH1 and IDH2 wild-type”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Gross et al., 2010
In the citing paper
“several samples with elevated 2HG were found to have neomorphic mutations at either IDH1 R132 or IDH2 R172 (Gross et al., 2010)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Gross et al., 2010
In the citing paper
“Enzymatic assays and measurement of 2HG levels in primary AML samples confirmed that these IDH2 R172 mutations result in 2HG elevation (Gross et al., 2010; Ward et al., 2010).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Gross et al., 2010
In the citing paper
“serum 2HG levels have successfully correlated with IDH1 R132 mutations in AML”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Gross et al., 2010
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Citations
Cites
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
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
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., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154
Self-citationRecurring 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
Isocitrate Dehydrogenase 1 Codon 132 Mutation Is an Important Prognostic Biomarker in Gliomas
Sanson, M., Marie, Y., Paris, S., Idbaïh, A., Laffaire, J., Ducray, F., Hallani, S. E., Boisselier, B., Mokhtari, K., Hoang‐Xuan, K., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.21.9832 · Cited by 1,049
Analysis of the IDH1 codon 132 mutation in brain tumors
Balss, J., Meyer, J., Mueller, W., Korshunov, A., Hartmann, C., & von Deimling, A. (2008) · Acta Neuropathologica · doi:10.1007/s00401-008-0455-2 · Cited by 1,036
IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas
Watanabe, T., Nobusawa, S., Kleihues, P., & Ohgaki, H. (2009) · The American Journal of Pathology · doi:10.2353/ajpath.2009.080958 · Cited by 1,027
Nishihara, K., Kanemori, M., Kitagawa, M., Yanagi, H., & Yura, T. (1998) · Applied and Environmental Microbiology · doi:10.1128/aem.64.5.1694-1699.1998 · Cited by 440
Xu, X., Zhao, J., Xu, Z., Peng, B., Huang, Q., Arnold, E., & Ding, J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404298200 · Cited by 407
Bleeker, F. E., Lamba, S., Leenstra, S., Troost, D., Hulsebos, T. J. M., Vandertop, W. P., Frattini, M., Molinari, F., Knowles, M. A., Cerrato, A., et al. (2009) · Human Mutation · doi:10.1002/humu.20937 · Cited by 365
Schnittger, S., Kern, W., Tschulik, C., Weiss, T., Dicker, F., Falini, B., Haferlach, C., & Haferlach, T. (2009) · Blood · doi:10.1182/blood-2009-03-213389 · Cited by 332
Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers
Kang, M. R., Kim, M. S., Oh, J. E., Kim, Y. R., Song, S. Y., Seo, S. I., Lee, J. Y., Yoo, N. J., & Lee, S. H. (2009) · International Journal of Cancer · doi:10.1002/ijc.24379 · Cited by 312
Overexpression of Trigger Factor Prevents Aggregation of Recombinant Proteins in Escherichia coli
Nishihara, K., Kanemori, M., Yanagi, H., & Yura, T. (2000) · Applied and Environmental Microbiology · doi:10.1128/aem.66.3.884-889.2000 · Cited by 306
Miyauchi, J., Kelleher, C. A., Yang, Y., Wong, G. G., Clark, S., Minden, M., Minkin, S., & McCulloch, E. A. (1987) · Blood · doi:10.1182/blood.v70.3.657.657 · Cited by 208
Self-citationl ‐2‐Hydroxyglutaric aciduria, a defect of metabolite repair
Rzem, R., Vincent, M., SCHAFTINGEN, E. V., & Veiga‐da‐Cunha, M. (2007) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-007-0487-0 · Cited by 149
Analysis of IDH1 and IDH2 mutations in Japanese glioma patients
Sonoda, Y., Kumabe, T., Nakamura, T., Saito, R., Kanamori, M., Yamashita, Y., Suzuki, H., & Tominaga, T. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2009.01270.x · Cited by 140
IDH1andIDH2Mutations in Gliomas
Carli, E. D., Wang, X.-W., & Puget, S. (2009) · New England Journal of Medicine · doi:10.1056/nejmc090593 · Cited by 134
Lu, W., Kimball, E., & Rabinowitz, J. D. (2005) · Journal of the American Society for Mass Spectrometry · doi:10.1016/j.jasms.2005.09.001 · Cited by 127
D‐2‐hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats
Latini, A., Scussiato, K., Rosa, R. B., Llesuy, S., Belló‐Klein, A., Dutra‐Filho, C. S., & Wajner, M. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02639.x · Cited by 112
D ‐2‐Hydroxyglutaric aciduria: Unravelling the biochemical pathway and the genetic defect
Struys, E. A. (2006) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-006-0317-9 · Cited by 89
Induction of oxidative stress by L‐2‐hydroxyglutaric acid in rat brain
Latini, A., Scussiato, K., Rosa, R. B., Leipnitz, G., Llesuy, S., Belló‐Klein, A., Dutra‐Filho, C. S., & Wajner, M. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10735 · Cited by 71
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Self-citationOtto 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
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Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233
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
Metadata
- Authors
- 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., Dang, L., Fantin, V. R., & Mak, T. W.
- Affiliations
- Agios Pharmaceuticals Incorporated, Cambridge, MA 02139 1
- University Health Network (CA)
- Agios Pharmaceuticals (United States) (US)
- Corresponding author
- Fantin, Valeria R.
- Mak, Tak W.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2010-02-08
- Volume
- 207
- Issue
- 2
- Pages
- 339-344
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2822606
- OpenAlex
- W2159731673
- Cited by
- 736
- References
- 23
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 34 · 2023: 35 · 2022: 29 · 2021: 55 · 2020: 40 · 2019: 36 · 2018: 45 · 2017: 51 · 2016: 61 · 2015: 44 · 2014: 49 · 2013: 61 · 2012: 61
- FWCI
- 45.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Leukemia and Lymphoma Society
- Agios Pharmaceuticals
- Terry Fox Foundation
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- 2-hydroxyglutarate, IDH mutation, acute myeloid leukemia, alpha-ketoglutarate, NADPH-dependent reduction, gain-of-function mutations, cancer metabolism, metabolic biomarkers
- MeSH terms
- Catalysis, Glutarates, Humans, Isocitrate Dehydrogenase, Ketoglutaric Acids, Mutation, NADP, Recombinant Proteins, Leukemia, Myeloid, Acute
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