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Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism
Open accessAbstract
Dysregulation of metabolism is a common phenomenon in cancer cells. The NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) function at a crossroads of cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction. We review the normal functions of the encoded enzymes, frequent mutations of IDH1 and IDH2 recently found in human cancers, and possible roles for the mutated enzymes in human disease. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2-4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are usually heterozygous in cancer, and they appear to confer a neomorphic enzyme activity for the enzymes to catalyze the production of D-2-hydroxyglutarate. Study of alterations in these metabolic enzymes may provide insights into the metabolism of cancer cells and uncover novel avenues for development of anticancer therapeutics.
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“There is a renewed interest in the area of cancer metabolism with metabolic reprogramming coined as a hallmark of cancer based on the discovery of mutations and alterations in IDH1 and IDH2 along with succinate dehydrogenase (SDH), fumarate hydratase (FH), and pyruvate kinase M2 (PKM2) [41, 42].”
From Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells (2018) · cites this paper as [42]
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“Catalysis of isocitrate to α-ketoglutarate (α-KG) and reduction of NAD(P) + to NAD(P)H are induced by Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2), metabolic enzymes in the TCA cycle (Reitman and Yan 2010).”
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“8,10 2-Hydroxyglutarate is an oncometabolite, which is an important allosteric regulator and a cofactor in chromatin remodeling and in mitochondrial respiration, angiogenesis, and cancer cell survival.(11,15,19) The recent discovery of IDH mutations in gliomas has opened up a new avenue of research in brain tumors, as…”
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“Isocitrate dehydrogenase, an NADP+-dependent enzyme, which decarboxylates isocitrate to a-ketoglutarate in the TCA cycle, has been found to carry heterozygous mutations in the prostate including other cancers such as acute myeloid leukaemia (AML) (64).”
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“or modulating the activity of metabolic and epigenetic tumor suppressor enzymes that use the structurally similar metabolite a-ketoglutarate as a cosubstrate [11, 14, 24].”
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“[9–11] While the wild-type IDH1 catalyzes the oxidative decarboxylation of isocitrate and produces alpha-ketoglutarate (alpha-KG) in the tricarboxylic acid cycle,[12] the mutant IDH1 converts alpha-KG further into 2-hydroxyglutarate, which,”
New clues in the malignant progression of glioblastoma: can thioredoxin system play a role?
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“IDH1 is localized primarily in the cytosol and peroxisomes, where it plays an important role in maintaining NADPH levels, which are critical for the redox balance that is established by the glutathione and thioredoxin systems [2,3].”
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“IDH1 is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate and plays an important role in the cellular protection from oxidative stress [8].”
The Distribution and Significance of IDH Mutations in Gliomas
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“This gene, localized in the mitochondria, plays a key role in the regulation of the tricarboxylic acid cycle and, like IDH1, has been shown to have a protective role against insults such as oxidative stress (Lee et al. 2004; Reitman and Yan 2010).”
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“Mutations of two such factors in SRSF2 and U2AF1 have been identified as high molecular risk mutations in myelofibrosis as both are associated with lower median overall survival compared with wildtype [49,66,67].”
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LncRNA IDH1-AS1 suppresses cell proliferation and tumor growth in glioma
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“The metabolic enzymes encoded by IDH1 genes convert isocitrate to α-ketoglutarate, producing NADPH, and participate in glucose sensing, lipid metabolism, and oxidative respiration [43], and the activity of these enzymes are shown to protect against replicative senescence by reducing oxidative DNA damage.”
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“IDH1 encodes the NADP (+)-dependent metabolic enzyme isocitrate dehydrogenase, which is involved in the citric acid cycle [30].”
BackgroundUpdate for astrocytomas: medical and surgical management considerations
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“In most cases, the IDH1 and IDH2 mutations are mutually exclusive (Reitman and Yan 2010; Papaemmanuil et al., 2016).”
BackgroundIDH-mutant gliomas in children and adolescents - from biology to clinical trials
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“Under normal physiological conditions, the isoenzymes IDH1 and IDH2 help regulate cellular metabolism within distinct cellular compartments—IDH1 functions in the cytoplasm and peroxisomes, whereas IDH2 is catalytically active in the mitochondria [32] (Fig.”
Probing altered enzyme activity in the biochemical characterization of cancer
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IDH2 mutations in acute myeloid leukemia
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“…and IDH2 are NADP + - dependent enzymes that play a major role in NADPH generation, cellular respiration, and protection against oxidative stress [6,8,9]. therefore, it is believed that the loss of function of IDH1 and IDH2 negatively impacts detoxification mechanisms, resulting in DNA damage and…”
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“decreased NADPH production, which probably predisposes cells to oxidative stress.[44] Elevated levels of D-2HG in IDHmut Figure 1: e World Health Organization Central Nervous System 5.”
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Phosphorylation of IDH1 Facilitates Progestin Resistance in Endometrial Cancer
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Genetic and Epigenetic Alterations in Primary–Progressive Paired Oligodendroglial Tumors
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“Mutation of isocitrate dehydrogenases 1 and 2 genes (IDH1 and IDH2), which catalyze the oxidative decarboxylation of isocitrate to a-ketoglutarate, has been associated with improved survival in glioma patients [4,5].”
BackgroundFeatures of intraventricular tanycytic ependymoma: report of a case and review of literature.
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AML multi-gene panel testing: A review and comparison of two gene panels
Thakral, G., Vierkoetter, K. R., Namiki, S., Lawicki, S., Fernandez, X., Ige, K., Kawahara, W., & Lum, C. (2016) · Pathology - Research and Practice · doi:10.1016/j.prp.2016.02.004 · Cited by 8
Kim, J. I., Noh, M. R., Yoon, G.-E., Jang, H., Kong, M. J., & Park, K. M. (2021) · Korean Journal of Physiology and Pharmacology · doi:10.4196/kjpp.2021.25.2.139 · Cited by 8
“Isocitrate dehydrogenases (IDHs) produce NAD(P) H by reduction of NAD(P) during oxidative decarboxylation of isocitrate to -ketoglutarate [8].”
BackgroundSong, M.-K., Park, B.-B., & Uhm, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115789 · Cited by 8
“IDH2 is localized in the mitochondria and operates within the citric acid cycle, while IDH1 promotes the same reaction within the cytoplasm [67].”
BackgroundLiu, W., Sun, Y., Ge, W., Zhang, F., Gan, L., Zhu, Y., Guo, T., & Liu, K. (2021) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2021.100187 · Cited by 8
“decarboxylation of isocitrate into α-ketoglutarate (α-KG ) in tricarboxylic acid cycle (TCA 188 cycle), and NADPH was synchronously produced at the biochemical process [52] (Fig.”
BackgroundZhang, W., Bai, H., Wang, Y., Wang, X., Jin, R., Guo, H., Lai, H., Tang, Y., & Wang, Y. (2024) · Pharmaceuticals · doi:10.3390/ph17030336 · Cited by 7
“Once mutation of IDH1 occurs, the conversion of α -KG to R-2-hydroxyglutaric (2-HG) acid catalyzed by mIDH1 [9].”
BackgroundTranscriptome meta-analysis of Kawasaki disease in humans and mice
Gu, W., Mirsaidi-Madjdabadi, S., Ramirez, F., Simonson, T. S., & Makino, A. (2024) · Frontiers in Pediatrics · doi:10.3389/fped.2024.1423958 · Cited by 7
Holst, J. M., Enemark, M. B., Pedersen, M. B., Lauridsen, K. L., Hybel, T. E., Clausen, M. R., Frederiksen, H., Møller, M. B., Nørgaard, P. H., Plesner, T. L., et al. (2021) · Cancers · doi:10.3390/cancers13215526 · Cited by 7
Azacitidine and its role in the upfront treatment of acute myeloid leukemia
Raslan, O. M., & Garcia‐Horton, A. (2022) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2022.2082284 · Cited by 7
“2-hydroxyglutatate (2HG), accumulation of which blocks cellular differentiation and promotes tumorigenesis [53,54].”
BackgroundA Targeted Next-Generation Sequencing Panel to Genotype Gliomas
Guarnaccia, M., Guarnaccia, L., Cognata, V. L., Navone, S. E., Campanella, R., Ampollini, A. M., Locatelli, M., Miozzo, M. R., Marfia, G., & Cavallaro, S. (2022) · Life · doi:10.3390/life12070956 · Cited by 8
Shayanfar, N., Zare‐Mirzaie, A., Mohammadpour, M., Jafari, E., Mehrtash, A., Emtiazi, N., & Tajik, F. (2022) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-022-04336-z · Cited by 8
“irreversibly and regulated by different allosteric effectors (Reitman and Yan 2010).”
BackgroundActivating Mutations and Targeted Therapy in Cancer
Tuna, M., & Christopher, I. L. (2012) · InTech eBooks · doi:10.5772/48701 · Cited by 8
“…MacConaill, Campbell et al. 2009; Yan, Parsons et al. 2009; de Muga, Hernandez et al. 2010; Gravendeel, Kloosterhof et al. 2010; Green and Beer 2010; Reitman and Yan 2010; Yen, Bittinger et al. 2010; Chapman, Lawrence et al. 2011; Konopka, Janiec-Jankowska et al. 2011; Metzger, Chambeau et al.…”
BackgroundPractical Molecular Pathologic Diagnosis of Infiltrating Gliomas
Pekmezci, M., & Perry, A. (2014) · Surgical pathology clinics · doi:10.1016/j.path.2014.10.004 · Cited by 7
Epigenetic aberrations in myeloid malignancies (Review)
Takahashi, S. (2013) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2013.1417 · Cited by 7
Commensal Microbiota Regulation of Metabolic Networks During Olfactory Dysfunction in Mice
Wang, H., Liu, L., Rao, X., Chai, T., Zeng, B., Zhang, X., Yu, Y., Zhou, C., Pu, J., Zhou, W., et al. (2020) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s236541 · Cited by 7
Lee, S.-Y., Kwon, J., & Lee, K. (2021) · Oncology Reports · doi:10.3892/or.2021.7998 · Cited by 7
“The enzymatic activities of the wild‐type and mutant forms of IDH1/IDH2 differ in the regulation of the TCA cycle (68).”
Promoter Methylation Analysis of IDH Genes in Human Gliomas
Flanagan, S., Lee, M. C., Li, C. C. Y., Suter, C. M., & Buckland, M. E. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00193 · Cited by 8
“Either loss-of-function or gain-of-function of IDH will result in reduced cytoplasmic NADPH levels and susceptibility to oxidative stress (Reitman and Yan, 2010).”
BackgroundValvi, S., Fouladi, M., Fisher, M. J., & Gottardo, N. G. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1662414 · Cited by 12
Acute myeloid leukemia in elderly patients: New targets, new therapies
Park, H. J., & Gregory, M. A. (2023) · Aging and Cancer · doi:10.1002/aac2.12065 · Cited by 8
Exploring the potential of nutraceutical to combat gliomas: focus on mIDH2 protein
Murali, P., & Karuppasamy, R. (2024) · Frontiers in Physics · doi:10.3389/fphy.2024.1345834 · Cited by 6
Nanotherapeutic strategy against glioblastoma using enzyme inhibitors
Thiruvengadam, R., Dareowolabi, B. O., Moon, E., & Kim, J. H. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117713 · Cited by 6
Ahmed, H. U., Paul, A. C., Mahmud, Z., Rahman, T., & Hosen, M. I. (2021) · Gene Reports · doi:10.1016/j.genrep.2021.101259 · Cited by 7
Carbohydrate metabolism I: glycolysis and the tricarboxylic acid cycle
Ha, C. E., & Bhagavan, N. V. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-88541-6.00030-2 · Cited by 6
Molecular mechanisms of hepatic lipid metabolism disorders: Focus on mitochondrial quality control
Yu, J., Huang, J., Xia, T., Li, M., & Li, R. (2024) · Portal hypertension & cirrhosis · doi:10.1002/poh2.95 · Cited by 6
Pessôa, I. A., Sagica, F. D. E. S., Anselmo, N. P., Brito, J. R. N., & de Oliveira, E. H. C. (2015) · Genetics and Molecular Research · doi:10.4238/2015.june.12.6 · Cited by 6
“IDH3 mutations have not been implicated in neoplasias (Reitman and Yan, 2010).”
BackgroundExpression patterns of members of the isocitrate dehydrogenase gene family in murine inner ear
Kim, Y.-R., Kim, K.-H., Lee, S., Oh, S.-K., Park, J.-W., Lee, K., Baek, J.-I., & Kim, U. (2017) · Biotechnic & Histochemistry · doi:10.1080/10520295.2017.1367034 · Cited by 6
“Therefore, regulation of ROS levels is important for preventing inner ear degeneration caused by ROS (Ohlemiller and Dugan 1999, Someya et al. 2010).”
BackgroundIDH1-mutated transgenic zebrafish lines: An in-vivo model for drug screening and functional analysis
Gao, Y., de Wit, M., Struys, E. A., van der Linde, H. C. Z., Salomons, G. S., Lamfers, M. L. M., Willemsen, R., Smitt, P. A. E. S., & French, P. J. (2018) · PLoS ONE · doi:10.1371/journal.pone.0199737 · Cited by 6
EGFRvIII expression and isocitrate dehydrogenase mutations in patients with glioma
Taher, M. M., Dairi, G., Butt, E., Alquthami, K. M., Alkhalidi, H., Jastania, R., Nageeti, T., Bogari, N. M., Athar, M., Al-Allaf, F. A., et al. (2020) · Oncology Letters · doi:10.3892/ol.2020.12247 · Cited by 6
“As compared with the IDH1 gene, muta‐ tions in the IDH2 gene are less prevalent in gliomas (40,45).”
ResultSoliman, M. E. S., Poonan, P., Peters, X. Q., Alahmdi, M. I., & Abo-Dya, N. E. (2022) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520623666221129163001 · Cited by 5
Metabolism and therapeutic response in acute myeloid leukemia with IDH1/2 mutations
Gabellier, L., Bosetta, E., Heiblig, M., & Sarry, J. (2025) · Trends in cancer · doi:10.1016/j.trecan.2025.01.011 · Cited by 6
Srinivasan, A., Zhou, Y., Scordino, T., Prabhu, S., Wierenga, A. M., Simon, G. A., Wierenga, K. J., Thompson, J., Shah, R. K., & Sinha, A. A. (2020) · Pediatric Hematology and Oncology · doi:10.1080/08880018.2020.1737284 · Cited by 4
“IDH1 protein also plays a role in the glucose-sensing pathway.(26) Increased”
BackgroundFan, X., Nie, X., Huang, J., Zhang, L., Wang, X., & Lu, M. (2022) · Journal of Oncology · doi:10.1155/2022/9886044 · Cited by 5
“IDH1 mutation is an early event in glioma development and positively correlates with TP53 mutation [90, 91].”
BackgroundPark, M. N. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512037 · Cited by 4
Blau, O. (2015) · InTech eBooks · doi:10.5772/60928 · Cited by 5
“Both genes function in a crossroads of cellular metabolism, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction [128].”
BackgroundWEE1 epigenetically modulates 5-hmC levels by pY37-H2B dependent regulation of IDH2 gene expression
Mahajan, N. P., Malla, P., Bhagwat, S., Sharma, V., Sarnaik, A., Kim, J., Pilon‐Thomas, S., Weber, J. S., & Mahajan, K. N. (2017) · Oncotarget · doi:10.18632/oncotarget.22374 · Cited by 5
“The isocitrate dehydrogenases, IDH1 and IDH2, catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), a critical regulator of cell metabolism [24, 25].”
IDH1/2 Mutations and BCL-2 Dependence: An Unexpected Chink in AML’s Armour
Pronier, E., & Levine, R. L. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.02.013 · Cited by 5
“Reitman and Yan (2010) noted depletion of the tricarboxylic acid (TCA) cycle metabolites citrate, cis-aconitate, a-KG, malate, and fumarate and an accumulation of biosynthetic precursors in cell lines that expressed IDH1 R132H and IDH2 R172K mutations, suggesting that 27, March 9, 2015 ª2015…”
BackgroundR132 mutations in canine isocitrate dehydrogenase 1 (IDH1) lead to functional changes
Kawakami, S., Ochiai, K., Azakami, D., Kato, Y., Michishita, M., Morimatsu, M., Ishiguro‐Oonuma, T., Onozawa, E., Watanabe, M., & Omi, T. (2017) · Veterinary Research Communications · doi:10.1007/s11259-017-9707-8 · Cited by 5
“Isocitrate dehydrogenases (IDHs) catalyse the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), and produce NAD (P) H from NAD (P)+. Eukaryotes have both NAD+- and NADP+-dependent IDHs (Reitman and Yan 2010).”
Background13C Flux Analysis in Biotechnology and Medicine
Cheah, Y. E., Hasenour, C. M., & Young, J. D. (2017) · Systems Biology · doi:10.1002/9783527696130.ch2 · Cited by 5
A niche-dependent redox rheostat regulates epithelial stem cell fate
Chen, X., Raghunathan, K., Bao, B., Ngwa, E. M., Kwong, A., Wu, Z., Babcock, S. J., Baek, C., Ye, G., Muppirala, A. N., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-66636-5 · Cited by 4
Resistance to Targeted Therapy in AML: Current Challenges and Emerging Treatment Strategies
Stafylidis, C., & Diamantopoulos, P. T. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15062171 · Cited by 4
“Furthermore, α -KG possesses antioxidant properties, and the produced NADPH helps maintain cellular redox balance by reducing glutathione through glutathione reductase [189].”
Brain Tumor Metabolism — Unraveling Its Role in Finding New Therapeutic Targets
Miranda‐Gonçalves, V., Baltazar, F., & Reis, R. M. (2015) · InTech eBooks · doi:10.5772/59606 · Cited by 5
“Isocitrate Dehydrogenase (IDH) IDH is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketogluta‐ rate, generating NADH in the mitochondria or NADPH in the cytoplasm [75].”
BackgroundGenetic Alterations of Glioblastoma
Richterová, R., & Kolarovszki, B. (2016) · InTech eBooks · doi:10.5772/63127 · Cited by 7
“Also, IDH2 mutation, which is much less frequent than IDH1 mutation, occurs in gliomas [51], but only in about 6% of secondary GBMs [52].”
Dittakavi, S., Jat, R. K., Mallurwar, S. R., Jairam, R. K., & Mullangi, R. (2019) · ADMET & DMPK · doi:10.5599/admet.648 · Cited by 4
“All three isoforms are responsible for the production of nicotinamide adenine dinucleotide phosphate (NADPH) from NADP by catalyzing the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) [1].”
Background
Metadata
- Authors
- Reitman, Z. J., & Yan, H.
- Affiliations
- Duke University (US)
- Venue
- JNCI Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-05-31
- Volume
- 102
- Issue
- 13
- Pages
- 932-941
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- PMC
- PMC2897878
- OpenAlex
- W2124951199
- Cited by
- 562
- References
- 88
- Citations by year
- 2026: 22 · 2025: 41 · 2024: 20 · 2023: 33 · 2022: 31 · 2021: 44 · 2020: 40 · 2019: 43 · 2018: 40 · 2017: 36 · 2016: 31 · 2015: 34 · 2014: 28 · 2013: 34 · 2012: 38
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Cancer Institute (R01CA118822, R01CA140316)
- National Institute of General Medical Sciences (T32GM007171)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- IDH1, IDH2, IDH1 mutation, IDH2 mutation, cancer metabolism, glioma, acute myeloid leukemia, D-2-hydroxyglutarate, oxidative stress, lipogenesis, oxygen sensing, anticancer agents
- MeSH terms
- Animals, Hypoxia, Arginine, Brain Neoplasms, Codon, Glioblastoma, Glucose, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, NADP, Neoplasms, Oligodendroglioma, Oncogenes, Signal Transduction, Up-Regulation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor
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