The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate

By Patrick S. Ward, Jay L. Patel, David R. Wise, O. Abdel-Wahab, Bryson D. Bennett, Hilary A. Coller, J. Cross, V. Fantin, C. Hedvat, A. Perl and 6 more. Cancer Cell, 2010

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SUMMARY The somatic mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) observed in gliomas can lead to the production of 2-hydroxyglutarate (2HG). Here, we report that tumor 2HG is elevated in a high percentage of patients with cytogenetically normal acute myeloid leukemia (AML). Surprisingly, less than half of cases with elevated 2HG possessed IDH1 mutations. The remaining cases with elevated 2HG had mutations in IDH2, the mitochondrial homolog of IDH1. These data demonstrate that a shared feature of all cancer-associated IDH mutations is production of the onco-metabolite 2HG. Furthermore, AML patients with IDH mutations display a significantly reduced number of other well characterized AML-associated mutations and/or associated chromosomal abnormalities, potentially implicating IDH mutation in a distinct mechanism of AML pathogenesis.

Subfields: Cancer Research, Genetics, Hematology

View Paper: https://www.semanticscholar.org/paper/b1fe911740b7c921a74d685388a426d6a7dd3836

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Citations in the corpus

Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. (2011, positive): “Additional work is required to determine which cancer cells rely on NADPH production via IDH1, malic enzyme, and/or the oxidative pentose phosphate pathway.”
IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype (2012, background): “Mutation of IDH imparts the ability to produce 2-hydroxyglutarate (2-HG), a potential oncometabolit”
The oncometabolite 2‐hydroxyglutarate inhibits histone lysine demethylases (2011, background): “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).”
Durable Remissions with Ivosidenib in IDH1‐Mutated Relapsed or Refractory AML (2018, neutral): “In CEBPA 3/119 (3) 4/172 (2) 5/245 (2) Table 1.”
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, methodology): “Likewise, following the discovery of 2HG-producing IDH2 R140 mutations in leukemia, researchers looked for and successfully found germline IDH2 R140 mutations in D-2HG aciduria.”
Glutaminolysis: A Hallmark of Cancer Metabolism. (2017, background): “Two types of enzymes that are inhibited in this manner are DNA demethylases and histone demethylases; their inhibition results in hypermethylation of DNA CpG islands and histone lysine residues, leading to genome-wide epigenetic alterations (79, 117, 118).”
Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, background): “2-HG inhibits the enzymatic activity of these enzymes by competing with their cosubstrate, 2OG (Dang et al. 2009; Gross et al. 2010; Ward et al. 2010; W Xu et al. 2011).”
The role of mutations in epigenetic regulators in myeloid malignancies (2012, background): “Follow-up candidate-gene sequencing efforts later found IDH2 mutations in glioma and in AML (55, 56).”
The Definition of Primary and Secondary Glioblastoma (2012, background): “Importantly, IDH1/2mutations are gain-of-function mutations that also produce the oncometabolite 2HG froma-KG (51, 52).”
Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases (2011, positive): “Recently, it was reported that expression of IDH1R132H suppresses TET2 activity and the mutations of IDH1 and IDH2 genes occur in a mutual exclusive manner with that of TET2 gene in AML (Figueroa et al., 2010).”