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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
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IDH1 and IDH2 Mutations in Gliomas
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Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
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Self-citationThe Consensus Coding Sequences of Human Breast and Colorectal Cancers
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“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
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“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
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“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
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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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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