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The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate
Open accessAbstract
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 oncometabolite 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.
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In the 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).”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
What the sources say
- Not checked yetcites Dang et al., 2009 source
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In the paper
“None of the IDH2-mutated samples were found to also have somatic mutations in Flt-3, NPM1, or ASXL1”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 mutations are more common than IDH1 mutations in AML
Strength:plain· not yet calibratedn = 78Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IDH2 siRNA treated cells displayed a significant reduction in levels of citrate +5”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is critical for proliferating cells and contributes to the conversion of α-ketoglutarate into citrate in the mitochondria
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In the paper
“2HG production is a shared feature of heterozygous mutations in either cytosolic IDH1 or mitochondrial IDH2.”
- Also stated in: § 2HG as an onco-metabolite · plain
“All IDH mutations reported to date share the neomorphic ability to produce high levels of tumor 2HG.”
- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
“Here we report that the common feature of IDH1 and IDH2 mutations observed in AML and glioma is the acquisition of an enzymatic activity not shared by either wild-type enzyme.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § 2HG as an onco-metabolite · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we noted a trend towards improved survival in patients who presented with IDH2 mutations (p=0.08, Figure S2B)”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 mutations are more common than IDH1 mutations in AML
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In the paper
“All samples displaying a signal ratio for 2HG/glutamate > 1% had either an IDH1 or IDH2 mutation”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > 2HG can be used as a screening test for neomorphic IDH mutants
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In the paper
“extracts from cells expressing the R172K mutant IDH2 did not display isocitrate-dependent NADPH production above the levels observed in extracts from vector-transfected cells”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Mutation of IDH2 R172K enhances α-ketoglutarate-dependent NADPH consumption
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“none of the samples with a 2HG/glutamate signal ratio ≤ 1% had an IDH mutation”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > 2HG can be used as a screening test for neomorphic IDH mutants
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In the paper
“IDH2 R172K expressing cells were found to have an approximately 100-fold increase in the intracellular levels of 2HG compared with the levels detected in vector-transfected and IDH2 wild-type overexpressing cells”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Mutation of IDH2 R172K results in elevated 2HG levels
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“despite the reduced ability to bind isocitrate, the R140Q mutant IDH2 is predicted to maintain its ability to bind and orient α-ketoglutarate in the active site”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > 2HG can be used as a screening test for neomorphic IDH mutants
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- It may state two separate claims as one. 10
- Probably not a substantial claim. 17
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In addition, it appears that both wild-type IDH1 and IDH2 can play positive and non-redundant roles in cell proliferation.”
- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
“Both wild-type IDH1 and IDH2 are required for cell proliferation.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While IDH1 mutations were found in 7.7% of samples in this analysis (6/78), twice as many mutations were detected in IDH2, at a frequency of 15.4% (12/78, p<0.05)”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 mutations are more common than IDH1 mutations in AML
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“IDH2 mutations are more common than IDH1 mutations in AML”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 mutations are more common than IDH1 mutations in AML
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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In the paper
“when cells were treated with one of two independent siRNAs against IDH3, there was a reproducible increase in citrate +5, while citrate +4 was unchanged”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is critical for proliferating cells and contributes to the conversion of α-ketoglutarate into citrate in the mitochondria
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Overall, IDH2 mutations appear more common than IDH1 mutations in AML.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Liquid chromatography-mass spectrometry (LC-MS)
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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In the paper
“Mutations in human cytosolic isocitrate dehydrogenase I (IDH1) occur somatically in >70% of grade II-III gliomas and secondary glioblastomas, and in 8.5% of acute myeloid leukemias (AML)”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > INTRODUCTION
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“These IDH1 R132 mutations were observed in 8.5% of AML patients studied, and a significantly higher percentage of mutation was observed in the subset of patients whose tumors lacked cytogenetic abnormalities”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > INTRODUCTION
What the sources say
- Not checked yetcites Mardis et al., 2009 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the 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”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is mutated in AML
What the sources say
- Not checked yetcites Dang et al., 2009 source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data support a role for IDH2 and not IDH3 in the conversion of α-ketoglutarate into citrate by reductive carboxylation in the mitochondria”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is critical for proliferating cells and contributes to the conversion of α-ketoglutarate into citrate in the mitochondria
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the 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)”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > INTRODUCTION
What the sources say
- Not checked yetcites Dang et al., 2009 source
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In the paper
“After redissolving samples in deionized water, citrate was detected on two different LC-MS approaches, both of which gave comparable results.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Liquid chromatography-mass spectrometry (LC-MS)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Human IDH2 has 97% homology with pig IDH2, and none of the 13 residues that are different (out of 418 total, excluding the N-terminal mitochondrial signal sequence) are found in the active site.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Structural modeling
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While the exact role of wild-type IDH2 in supporting cell growth will require further investigation, this requirement correlates with the ability of IDH2 to contribute to the conversion of α-ketoglutarate into citrate via a pathway of reductive carboxylation in the mitochondria of proliferating cells.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“For all experiments, OD340 changes in assay buffer lacking lysate protein were measured and subsequently subtracted from the OD340 changes measured in lysate replicates to arrive at final values.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Cell lysate based enzyme assays
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Actin antibody (Santa Cruz, sc1616) was also used to assess equal protein loading of Western blots.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Western blot
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In the paper
“Isotopomer distributions were simultaneously corrected for naturally occurring heavy isotopes of all elements in each mass fragment using a correction matrix as previously described (Weckwerth, 2007).”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Gas chromatography-mass spectrometry (GC-MS) analysis
What the sources say
- Not checked yetcites Weckwerth, 2007
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In the paper
“Identification of the 2HG metabolite peak was confirmed using standards obtained from Sigma.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Gas chromatography-mass spectrometry (GC-MS) analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“A PDB structure of pig IDH2 is available, with isocitrate in the active site (1LWD) (Ceccarelli et al., 2002).”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Structural modeling
What the sources say
- Not checked yetcites Ceccarelli et al., 2002 source
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In the paper
“for samples with less than 70% blasts flow cytometric sorting (FACSAria) was used to isolate blast cells according to leukemic blast immunophenotype before DNA isolation.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Sequence Analysis of IDH1 and IDH2
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In the paper
“Wild-type and mutant sequences were then subcloned into pcDNA3 (Invitrogen) and confirmed by direct sequencing before expression in mammalian cells.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Constructing IDH1 and IDH2 mutants
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In the paper
“All DNA samples were whole genome amplified using Ø29 polymerase and mutations were validated on unamplified DNA to ensure all mutations were present in the diagnostic sample.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Sequence Analysis of IDH1 and IDH2
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“Sequence analysis was performed using Mutation Surveyor (SoftGenetics, State College PA) and all mutations were validated by repeat PCR and sequencing on unamplified DNA from the archival sample.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Sequence Analysis of IDH1 and IDH2
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Mitochondria typically have a high NADPH/NADP+ ratio, supported in part by the ability to interconvert NADPH and NADH in the matrix (Rydstrom, 2006).”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
What the sources say
- Not checked yetcites Rydstrom, 2006 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
All reported IDH1 or IDH2 mutations are heterozygous, with cancer cells retaining one wild-type copy of the relevant allele.
“To date, all reported IDH1 or IDH2 mutations are heterozygous, with the cancer cells retaining one wild-type copy of the relevant IDH1 or IDH2 allele”
The paper relies on this without support.
No patient has been reported with both an IDH1 and IDH2 mutation.
“No patient has been reported with both an IDH1 and IDH2 mutation”
The paper relies on this without support.
All reported IDH1 mutations result in an amino acid substitution at a single arginine residue in the enzyme's active site, R132.
“To date, all reported IDH1 mutations result in an amino acid substitution at a single arginine residue in the enzyme’s active site, R132”
The paper relies on this without support.
IDH2 mutations identified in gliomas occur at the analogous residue to IDH1 R132, IDH2 R172.
“The IDH2 mutations which have been identified in gliomas occur at the analogous residue to IDH1 R132, IDH2 R172”
The paper relies on this without support.
IDH1 contributes to cytosolic NADPH production.
“IDH1 contributes to cytosolic NADPH production.”
The paper relies on this without support.
Mitochondrial α-ketoglutarate levels are kept high by various anaplerotic substrates.
“In addition, mitochondrial α-ketoglutarate is maintained at high levels by a variety of anaplerotic substrates.”
The paper relies on this without support.
IDH mutations occur frequently in gliomas with mixed astrocytic and oligodendroglial features and in acute myeloid leukemias.
“a possibility by which 2HG might contribute to tumorigenesis emerges from consideration of the tumor subtypes in which IDH mutations are found with high frequency: gliomas with mixed astrocytic and oligodendroglial features, and acute myeloid leukemias.”
The paper relies on this without support.
In those two tumor types, disease centers on proliferation of relatively undifferentiated cells, and pathogenesis involves a differentiation block rather than only faster proliferation.
“In both cases, proliferation of a relatively undifferentiated cell population is central to the disease, and pathogenesis is marked by a block to differentiation rather than simply by an increase in proliferative rate.”
The paper relies on this without support.
Most enzyme mutations linked to cancer cause either loss of catalysis or constitutive activation.
“Most cancer-associated enzyme mutations result in either catalytic inactivation or constitutive activation.”
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?
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 Ward et al., 2010
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 [113]
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 Ward et al, 2010
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 Ward 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 Ward 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 Ward et al., 2010
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 [168]
In the citing paper
“In contrast to wild-type isocitrate dehydrogenases, which convert the TCA cycle metabolite isocitrate to α-ketoglutarate, a mutant form of IDH prefers to use α-ketoglutarate as a substrate, catalyzing its conversion to the D-enantiomer of 2-hydroxyglutarate (2-HG) (Dang et al., 2010; Ward et al., 2010).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Ward et al., 2010
In the citing paper
“For example, 2-HG acts as a competitive inhibitor of α-KG, and its production by mutant IDH1 consumes α-KG (81, 99), leading to reduced TET2 and JmjC activity in tumor cells (79, 80).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [99]
In the citing paper
“the common feature of this remaining subset of 2HG-elevated AMLs was another mutation in IDH2, occurring at R140 (Ward et al., 2010)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Ward 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 Ward et al., 2010
In the citing paper
“some 2HG-elevated AML samples lacked IDH1 R132 or IDH2 R172 mutations”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Ward et al., 2010
In the citing paper
“has been investigated since then as a way to produce citrate and fatty acids from α-ketoglutarate derived from glutamine (Holleran et al., 1995; Ward et al., 2010; Yoo et al., 2008)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Ward et al., 2010
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 Ward et al., 2010
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting ranges for tumor 2HG elevation
MinorOne section says both mutant proteins produce more than a 100-fold increase in tumor 2HG, while another says cancers with IDH mutations are consistently elevated by 10-100 fold. The stated upper bound does not accommodate an increase over 100-fold.
“Nevertheless, both mutant proteins lead to an over 100-fold increase in tumor 2HG accumulation.”
“The 2HG levels in cancers with IDH mutations are consistently 10–100 fold elevated over levels found in samples lacking mutations of IDH1 or IDH2.”
Citations
Cites
The PyMOL Molecular Graphics System
DeLano, W. L. (2002) · Medical Entomology and Zoology · Cited by 18,147
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-citationThe Consensus Coding Sequences of Human Breast and Colorectal Cancers
Sjöblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., Mandelker, D. L., Leary, R. J., Ptak, J., Silliman, N., et al. (2006) · Science · doi:10.1126/science.1133427 · Cited by 3,161 · cited 1×
“Mutations have also been reported in cancers of the colon and prostate (Kang et al., 2009; Sjoblom et al., 2006).”
BackgroundDeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., & Thompson, C. B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709747104 · Cited by 2,622 · cited 1×
“IDH1 is one of only three cytosolic enzymes that contribute to the NADPH production required for nucleotide and lipid biosynthesis during cell growth (DeBerardinis et al., 2007).”
BackgroundSelf-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 · cited 1×
“This is in contrast to the data reported for gliomas in which less than 5% of IDH mutations were in IDH2 (Hartmann et al., 2009; Yan et al., 2009).”
ResultGlioma-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 · cited 1×
“Therefore, it has been proposed that mutant IDH1 can act as a dominant negative against wild-type IDH1 function, resulting in a decrease in cytosolic a-ketoglutarate levels and leading to an indirect activation of the HIF-1a pathway (Zhao et al., 2009).”
BackgroundBajad, S. U., Lu, W., Kimball, E., Yuan, J., Peterson, C. N., & Rabinowitz, J. D. (2006) · Journal of Chromatography A · doi:10.1016/j.chroma.2006.05.019 · Cited by 593 · cited 1×
“Reactions used to monitor other TCA components have been described previously (Bajad et al., 2006).”
MethodSelf-citationAnalytical strategies for LC–MS-based targeted metabolomics
Lu, W., Bennett, B. D., & Rabinowitz, J. D. (2008) · Journal of Chromatography B · doi:10.1016/j.jchromb.2008.04.031 · Cited by 489 · cited 1×
“In both cases, LC separation was by reversed phase chromatography using tributylamine as an ion pairing agent (Lu et al., 2008; Luo et al., 2007) with ionization by negative electrospray at 23 kV.”
MethodSelf-citation
Flagged first, then by citations
1 of the 27 references couldn’t be matched to a known paper.
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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
“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”
BackgroundMetabolic 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
“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.”
BackgroundMethodInfluentialSelf-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
“Additional work is required to determine which cancer cells rely on NADPH production via IDH1, malic enzyme, and/or the oxidative pentose phosphate pathway.”
InfluentialFundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
“The most relevant point here is that D2HG production requires a neomorphic enzyme activity imparted to IDH1/IDH2 by specific active-site mutations (33, 34).”
BackgroundMitochondrial 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
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
“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).”
InfluentialFigueroa, 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-citationHypoxia-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
Wallace, D. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3365 · Cited by 2,404
From Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119
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-citationClonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing
Ding, L., Ley, T. J., Larson, D. E., Miller, C. A., Koboldt, D. C., Welch, J. S., Ritchey, J. K., Young, M. A., Lamprecht, T., McLellan, M. D., et al. (2012) · Nature · doi:10.1038/nature10738 · Cited by 1,993
DNMT3A Mutations in Acute Myeloid Leukemia
Ley, T. J., Ding, L., Walter, M. J., McLellan, M. D., Lamprecht, T., Larson, D. E., Kandoth, C., Payton, J. E., Baty, J., Welch, J., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1005143 · Cited by 1,983
Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia
Patel, J. P., Gönen, M., Figueroa, M. E., Fernandez, H. F., Sun, Z., Racevskis, J., Vlierberghe, P. V., Dolgalev, I., Thomas, S., Aminova, O., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1112304 · Cited by 1,990
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
“Mutation of IDH imparts the ability to produce 2-hydroxyglutarate (2-HG), a potential oncometabolit”
BackgroundSelf-citationThe 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
Vyas, S., Zaganjor, E., & Haigis, M. C. (2016) · Cell · doi:10.1016/j.cell.2016.07.002 · Cited by 1,735
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791
Small molecules in targeted cancer therapy: advances, challenges, and future perspectives
Zhong, L., Li, Y., Xiong, L., Wang, W., Wu, M., Yuan, T., Yang, W. M., Tian, C., Miao, Z., Wang, T., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00572-w · Cited by 1,813
Emerging applications of metabolomics in drug discovery and precision medicine
Wishart, D. S. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.32 · Cited by 1,543
Metabolic pathways promoting cancer cell survival and growth
Boroughs, L. K., & DeBerardinis, R. J. (2015) · Nature Cell Biology · doi:10.1038/ncb3124 · Cited by 1,492
Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia
Stein, E. M., DiNardo, C. D., Pollyea, D. A., Fathi, A. T., Roboz, G. J., Altman, J. K., Stone, R. M., DeAngelo, D. J., Levine, R. L., Flinn, I. W., et al. (2017) · Blood · doi:10.1182/blood-2017-04-779405 · Cited by 1,516
“Platelets, 310(9)/L 39 (1-372) 44 (1-507) 45 (1-644)”
Self-citationDurable 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
“In CEBPA 3/119 (3) 4/172 (2) 5/245 (2) Table 1.”
Targeting cancer metabolism: a therapeutic window opens
Heiden, M. G. V. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3504 · Cited by 1,443
Role of RNA modifications in cancer
Barbieri, I., & Kouzarides, T. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0253-2 · Cited by 1,350
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
“For example, 2-HG acts as a competitive inhibitor of a-KG, and its production by mutant IDH1 consumes a-KG (81, 99), leading to reduced TET2 and JmjC activity in tumor cells (79, 80).”
BackgroundLessons from the Cancer Genome
Garraway, L. A., & Lander, E. S. (2013) · Cell · doi:10.1016/j.cell.2013.03.002 · Cited by 1,377
“It soon became clear that the mutations caused a gain-of-function (or ‘‘neomorphic’’) activity, whereby isocitrate was converted to a distinct metabolite: the R-enantiomer of 2-hydroxyglutarate (2HG; Figure 1) (Dang et al., 2009; Ward et al., 2010).”
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
“In addition, recent work demonstrated that mutations in the metabolic enzymes IDH1 and IDH2 (Mardis et al., 2009; Parsons et al., 2008; Ward et al., 2010; Yan et al., 2009) are mutually exclusive with TET2 mutations, and that production of 2-hydroxyglutarate by neomorphic IDH1/2 mutant proteins (Dang et al.”
Self-citationReductive carboxylation supports growth in tumour cells with defective mitochondria
Mullen, A. R., Wheaton, W. W., Jin, E. S., Chen, P.-H., Sullivan, L. B., Cheng, T., Yang, Y., Linehan, W. M., Chandel, N. S., & DeBerardinis, R. J. (2012) · Nature · doi:10.1038/nature10642 · Cited by 1,328
Metabolomics 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
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
“Importantly, IDH1/2mutations are gain-of-function mutations that also produce the oncometabolite 2HG froma-KG (51, 52).”
BackgroundR-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
“IDH mutants induce a neomorphic enzymatic function that catalyzes the conversion of a-KG to the R enantiomer of 2-hydroxyglutarate (R-2HG) (Dang et al., 2009; Ward et al., 2010).”
BackgroundReversing 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
“Interestingly, TET2 mutations are found to be mutually exclusive with neomorphic mutations in IDH1/2 (R132 of IDH1 and R140/172 of IDH2) in AML (Dang et al., 2009; Ward et al., 2010).”
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
“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).”
BackgroundInfluentialGlutamine 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
Metabolic requirements for the maintenance of self-renewing stem cells
Ito, K., & Suda, T. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3772 · Cited by 1,014
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
Targeting 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 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).”
BackgroundTackling the cancer stem cells — what challenges do they pose?
Pattabiraman, D. R., & Weinberg, R. A. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4253 · Cited by 1,013
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
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
“data do not exclude a complementary role for cytosolic IDH1 in impacting reductive glutamine metabolism, potentially through its oxidative function in an IDH2/IDH1 shuttle that transfers high energy electrons in the form of NADPH from mitochondria to cytosol (16, 24).”
BackgroundSelf-citationInfluence 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
“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).”
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
“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).”
BackgroundMetabolic Regulation of Hematopoietic Stem Cells in the Hypoxic Niche
Suda, T., Takubo, K., & Semenza, G. L. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2011.09.010 · Cited by 844
Hartmann, 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
“In contrast, mutated IDH1 protein gains a novel function enabling the conversion of α-ketoglutarate to 2-hydroxyglutarate in a NADPH-consuming manner [5, 21].”
BackgroundTargeted 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-citationShort, N. J., Rytting, M., & Cortes, J. E. (2018) · The Lancet · doi:10.1016/s0140-6736(18)31041-9 · Cited by 839
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
“D2HG is the major form in diseases with IDH1 or IDH2 mutants (Dang et al., 2009; Gross et al., 2010).”
BackgroundInfluentialLoss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma
Lian, C. G., Xu, Y., Ceol, C., Wu, F., Larson, A., Dresser, K., Xu, W., Tan, L., Hu, Y., Zhan, Q., et al. (2012) · Cell · doi:10.1016/j.cell.2012.07.033 · Cited by 789
“These data suggest that IDH2, but not IDH1, is specifically downregulated in melanomas and that the WT IDH2 acts as a putative tumor suppressor in the zebrafish melanoma model, although the IDH family of enzymes has been considered candidate oncogenes in various tumors (Ward et al., 2010; Wrzeszczynski et al., 2011).”
BackgroundGlioblastoma: pathology, molecular mechanisms and markers
Aldape, K., Zadeh, G., Mansouri, S., Reifenberger, G., & von Deimling, A. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1432-1 · Cited by 735
“[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].”
BackgroundBorger, 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-citationMetabolic 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
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 Regulation of Epigenetics
Lu, C., & Thompson, C. B. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.06.001 · Cited by 699
“Indeed, metabolomic and biochemical analysis revealed that mutant IDHs display a neomorphic activity of producing 2-hydroxyglutarate (2HG) from aKG (Dang et al., 2009a; Ward et al., 2010).”
BackgroundSelf-citation( 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
The 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 695
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
“Notably, glutamine is an indispensable donor of reduced nitrogen for building both purine and pyrimidine bases (Wise & Thompson, 2010).”
Self-citationMetabolomics 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
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
“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).”
BackgroundIDH 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
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
“Follow-up candidate-gene sequencing efforts later found IDH2 mutations in glioma and in AML (55, 56).”
BackgroundSelf-citationMechanisms 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
“Examples of divergent pathways include (R)-2HG accumulation in tumors with IDH1 or IDH2 mutations, or metabolic preferences that differentiate tumors with distinct oncogenotypes (Dang et al., 2009; Shackelford et al., 2013; Ward et al., 2010).”
BackgroundSomatic mutations precede acute myeloid leukemia years before diagnosis
Desai, P., Mencia-Trinchant, N., Savenkov, O., Simon, M. S., Cheang, G., Lee, S., Samuel, M., Ritchie, E. K., Guzman, M. L., Ballman, K. V., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0081-z · Cited by 619
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
Self-citationTracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells
Lewis, C. A., Parker, S. J., Fiske, B. P., McCloskey, D., Gui, D. Y., Green, C. R., Vokes, N. I., Feist, A. M., Vander Heiden, M. G., & Metallo, C. M. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.008 · Cited by 562
“For instance, compartment-specific metabolic cycling through citrate/aKG (Sazanov and Jackson, 1994; Ward et al., 2010), malate/pyruvate (Jiang et al., 2013; Son et al., 2013), proline (Hagedorn and Phang, 1983; Nilsson et al., 2014), and serine (Tibbetts and Appling, 2010) have been suggested to…”
BackgroundIsocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia
Chan, S. M., Thomas, D., Corces, M. R., Xavy, S., Rastogi, S., Hong, W., Zhao, F., Medeiros, B. C., Tyvoll, D. A., & Majeti, R. (2015) · Nature Medicine · doi:10.1038/nm.3788 · Cited by 597
Regulation of the pentose phosphate pathway in cancer
Jiang, P., Du, W., & Wu, M. (2014) · Protein & Cell · doi:10.1007/s13238-014-0082-8 · Cited by 587
“A possible explanation for this observation is that mutant IDH1 and IDH2 proteins not only lose the ability to catalyze the isocitrate–α-KG reaction but also convert α-KG to R(-)-2-hydroxyglutarate ([R]-2HG) by expending NADPH (Dang et al., 2010; Ward et al., 2012; Ward et al., 2010).”
BackgroundMolecular Genetics of Adult Acute Myeloid Leukemia: Prognostic and Therapeutic Implications
Marcucci, G., Haferlach, T., & Döhner, H. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.30.2554 · Cited by 575
What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer
Losman, J.-A., & Kaelin, W. G. (2013) · Genes & Development · doi:10.1101/gad.217406.113 · Cited by 570
Emerging insights into the molecular and cellular basis of glioblastomaPreprint
Dunn, G. P., Rinne, M. L., Wykosky, J., Genovese, G., Quayle, S. N., Dunn, I. F., Agarwalla, P. K., Chheda, M. G., Campos, B., Wang, A., et al. (2012) · Genes & Development · doi:10.1101/gad.187922.112 · Cited by 573
“(2010) showed that mutant cells contained extremely high levels of 2-HG, which was also found in primary IDH1 mutant gliomas and in the serum of IDH mutant AML patients (Gross et al. 2010; Ward et al. 2010).”
BackgroundReitman, Z. J., & Yan, H. (2010) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djq187 · Cited by 562
Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge
Sturm, D., Bender, S., Jones, D. T. W., Lichter, P., Grill, J., Becher, O., Hawkins, C., Majewski, J., Jones, C., Costello, J. F., et al. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3655 · Cited by 555
Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
Bunse, L., Pusch, S., Bunse, T., Sahm, F., Sanghvi, K., Friedrich, M., Alansary, D., Sonner, J. K., Green, E., Deumelandt, K., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0095-6 · Cited by 566
Malignant Glioma: Lessons from Genomics, Mouse Models, and Stem Cells
Chen, J., McKay, R. M., & Parada, L. F. (2012) · Cell · doi:10.1016/j.cell.2012.03.009 · Cited by 549
“Subsequent studies reported a dominant-negative role for IDH1 R132 and suggested a tumor suppressor function for IDH1/2 (Zhao et al., 2009).”
BackgroundMethodInfluentialHypoxia Induces Production of L-2-Hydroxyglutarate
Intlekofer, A. M., Dematteo, R. G., Venneti, S., Finley, L. W. S., Lu, C., Judkins, A. R., Rustenburg, A. S., Grinaway, P. B., Chodera, J. D., Cross, J. R., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.023 · Cited by 513
“Chiral derivatization was performed to allow separation of 2HG enantiomers by GC-MS.”
InfluentialSelf-citationTefferi, A. (2010) · Leukemia · doi:10.1038/leu.2010.69 · Cited by 544
Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1
Seltzer, M. J., Bennett, B. D., Joshi, A. D., Gao, P., Thomas, A. G., Ferraris, D. V., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Rabinowitz, J. D., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1666 · Cited by 528
Self-citationEpigenetic Therapies for Cancer
Bates, S. E. (2020) · New England Journal of Medicine · doi:10.1056/nejmra1805035 · Cited by 503
Interplay between Metabolism and Epigenetics: A Nuclear Adaptation to Environmental Changes
Etchegaray, J., & Mostoslavsky, R. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.05.029 · Cited by 546
“Thus, DNA methylation can be enzymatically reversed upon TET-mediated oxidations of 5mC (Weber et al., 2016).”
BackgroundIDH mutations in cancer and progress toward development of targeted therapeutics
Dang, L., Yen, K., & Attar, E. C. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw013 · Cited by 509
Glioblastoma: From Molecular Pathology to Targeted Treatment
Cloughesy, T. F., Cavenee, W. K., & Mischel, P. S. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130324 · Cited by 531
Regulation and function of the mammalian tricarboxylic acid cycle
Arnold, P. K., & Finley, L. W. S. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102838 · Cited by 535
“By blocking the enzymatic activity of histone and DNA demethylases, D-2HG can function to lock cells in a hypermethylated state that blocks differentiation and reinforces a malignant and stem cell–like phenotype (30, 172–174).”
BackgroundIvosidenib and Azacitidine in IDH1 -Mutated Acute Myeloid Leukemia
Montesinos, P., Récher, C., Vives, S., Zarzycka, E., Wang, J., Bertani, G., Heuser, M., Calado, R. T., Schuh, A. C., Yeh, S., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2117344 · Cited by 568
Sykes, D. B., Kfoury, Y. S., Mercier, F. E., Wawer, M. J., Law, J. M., Haynes, M. K., Lewis, T. A., Schajnovitz, A., Jain, E., Lee, D., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.057 · Cited by 500
“Thus, DHO is a marker of enzyme inhibition, not an oncometabolite like 2-hydroxyglutarate (2HG) in patients with IDH mutant leukemias (Ward et al., 2010).”
Mitochondrial Dysfunction in Cancer
Boland, M. L., Chourasia, A. H., & Macleod, K. F. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00292 · Cited by 521
“Mutation of these genes in cancer leads to a buildup of their substrates; fumarate and succinate in the case of FH and SDH mutations (6,226),or conversion of their regular substrate to a new“oncometabolite” in the case of mutant IDH1/IDH2 converting isocitrate to 2-hydroxyglutarate (229, 231).”
BackgroundEmerging Roles for Branched-Chain Amino Acid Metabolism in Cancer
Sivanand, S., & Heiden, M. G. V. (2020) · Cancer Cell · doi:10.1016/j.ccell.2019.12.011 · Cited by 498
“…by mutant IDH is slow relative to many other cellular reactions that use αKG (Dexter et al., 2018), and mutant IDH does not change αKG levels in all settings (Dang et al., 2009; Ward et al., 2010), arguing other hypotheses may be needed to explain low BCAT expression in IDH mutant glioma.”
BackgroundEmerging patterns of somatic mutations in cancer
Watson, I. R., Takahashi, K., Futreal, P. A., & Chin, L. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3539 · Cited by 497
Miller, C. A., White, B. S., Dees, N. D., Griffith, M., Welch, J. S., Griffith, O. L., Vij, R., Tomasson, M. H., Graubert, T. A., Walter, M. J., et al. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003665 · Cited by 461
Metabolite Measurement: Pitfalls to Avoid and Practices to Follow
Lu, W., Su, X., Klein, M. S., Lewis, I. A., Fiehn, O., & Rabinowitz, J. D. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044952 · Cited by 467
Self-citationAG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
Yen, K., Travins, J., Wang, F., David, M. D., Artin, E., Straley, K., Padyana, A., Gross, S., DeLaBarre, B., Tobin, E., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1034 · Cited by 471
Self-citationMYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis
Terunuma, A., Putluri, N., Mishra, P., Mathé, E. A., Dorsey, T. H., Yi, M., Wallace, T. A., Issaq, H. J., Zhou, M., Killian, J. K., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci71180 · Cited by 428
Ross, J. S., Wang, K., Gay, L. M., Al-Rohil, R. N., Rand, J. V., Jones, D., Lee, H. J., Sheehan, C. E., Otto, G. A., Palmer, G. A., et al. (2014) · The Oncologist · doi:10.1634/theoncologist.2013-0352 · Cited by 453
Oxygen availability and metabolic adaptations
Nakazawa, M. S., Keith, B., & Simon, M. C. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.84 · Cited by 446
Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities
Cairns, R. A., & Mak, T. W. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0083 · Cited by 452
Yu, W., Dittenhafer‐Reed, K. E., & Denu, J. M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.355206 · Cited by 452
Gaidzik, V. I., Bullinger, L., Schlenk, R. F., Zimmermann, A., Röck, J., Paschka, P., Corbacioglu, A., Krauter, J., Schlegelberger, B., Ganser, A., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.30.7926 · Cited by 462
IDH1andIDH2Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives
Yang, H., Ye, D., Guan, K., & Xiong, Y. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1773 · Cited by 477
Metadata
- Authors
- Ward, 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., Rabinowitz, J. D., Carroll, M., Su, S. M., Sharp, K. A., Levine, R. L., & Thompson, C. B.
- Affiliations
- Abramson Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Princeton University (US)
- Agios Pharmaceuticals (United States) (US)
- University of Pennsylvania (US)
- Corresponding author
- Thompson, Craig B.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-03
- Volume
- 17
- Issue
- 3
- Pages
- 225-234
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC2849316
- OpenAlex
- W1995675594
- Cited by
- 2,020
- References
- 27
- Citations by year
- 2026: 76 · 2025: 68 · 2024: 113 · 2023: 102 · 2022: 111 · 2021: 149 · 2020: 137 · 2019: 148 · 2018: 133 · 2017: 127 · 2016: 151 · 2015: 140 · 2014: 110 · 2013: 126 · 2012: 126
- FWCI
- 90.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- University of Pennsylvania
- Memorial Sloan-Kettering Cancer Center
- Agios Pharmaceuticals
- National Cancer Institute (P01CA104838, R01CA092660, R01CA105463)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- IDH1 mutation, IDH2 mutation, 2-hydroxyglutarate, acute myeloid leukemia, oncometabolites, alpha-ketoglutarate, isocitrate dehydrogenase, chromosomal abnormalities, glioma
- MeSH terms
- Glutarates, Humans, Isocitrate Dehydrogenase, Isocitrates, Ketoglutaric Acids, Mitochondria, Mutation, Tumor Cells, Cultured, Leukemia, Myeloid, Acute, Cell Proliferation
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