Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations

By Stefan Gross, R. Cairns, M. Minden, E. Driggers, M. Bittinger, H. G. Jang, M. Sasaki, Shengfang Jin, D. Schenkein, Shinsan M. Su and 3 more. Journal of Experimental Medicine, 2010

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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.

Subfields: Cancer Research, Genetics, Hematology

View Paper: https://www.semanticscholar.org/paper/e645b94b7a237446ecf898e4828d0f18ebcd9303

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Citations in the corpus

Otto Warburg's contributions to current concepts of cancer metabolism (2011, background): “In addition to the familial cancer syndromes associated with OXPHOS mutations, somatic mutations of IDH1 (which is cytosolic) and IDH2 (which is mitochondrial) have been found in 80% of low-grade gliomas and 30% of karyotypically normal acute myelogenous leukaemia”
Glioblastoma: pathology, molecular mechanisms and markers (2015, background): “[31] showed that IDH1/2 mutant cells had high levels of 2-HG, as is also found in primary IDH1 mutant gliomas and in the serum of IDH1/2 mutant acute myeloid leukemia (AML) patients [54, 169].”
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).”
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “AML samples with low to undetectable 2HG were subsequently sequenced and determined to be IDH1 and IDH2 wild-types, and several samples with elevated 2HG were found to have neomorphic mutations at either IDH1 R132 or IDH2 R172 (Gross et al., 2010).”
Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia (2011, background): “Notably, we found that several HOX family genes and the IDH1 (isocitrate dehydrogenase 1), which are associated with acute myeloid leukemia pathogenesi”
Targeting cancer metabolism: a therapeutic window opens (2011, background): “, and lead to the production of D -2-hydroxyglutarate (2HG) — a metabolite that is only found at very low levels in normal cell”
Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “D2HG is the major form in diseases with IDH1 or IDH2 mutants (Dang et al., 2009; Gross et al., 2010).”
Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases (2011, neutral): “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).”
Influence of Metabolism on Epigenetics and Disease (2013, neutral): “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).”
Regulation of cancer cell metabolism (2011, background): “Subsequent studies revealed that IDH1 or IDH2 is mutated in approximately 80% of adult grade II and grade III gliomas and secondary glioblastomas, and in approximately 30% of cytogenetically normal cases of AM”