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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- Findingcitation
There is a marked difference between the rate of isocitrate-dependent NADPH production by wild-type IDH1/IDH2 and the rate of α-ketoglutarate-dependent NADPH consumption by the mutant proteins.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dang et al., 2009 source
Not checked in the free run.
- Findingown data
None of the IDH2-mutated samples had somatic mutations in Flt-3, NPM1, or ASXL1.
“None of the IDH2-mutated samples were found to also have somatic mutations in Flt-3, NPM1, or ASXL1”
Quote in the paperNot a substantial claim - Findingown data
IDH2 siRNA treated cells displayed a significant reduction in levels of citrate +5.
“IDH2 siRNA treated cells displayed a significant reduction in levels of citrate +5”
Quote in the paperSubstantial claim - Findingown data
IDH1 and IDH2 mutations in cancer share a neomorphic enzymatic activity that produces 2HG.
“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.”
Quote in the paperSubstantial claim - Also stated in: § 2HG as an onco-metabolite · plain
- Findingown data
There was a trend towards improved survival in patients who presented with IDH2 mutations (p=0.08).
“we noted a trend towards improved survival in patients who presented with IDH2 mutations (p=0.08, Figure S2B)”
Quote in the paperNot a substantial claim
- Findingown data
All samples displaying a 2HG/glutamate signal ratio >1% had either an IDH1 or IDH2 mutation.
“All samples displaying a signal ratio for 2HG/glutamate > 1% had either an IDH1 or IDH2 mutation”
Quote in the paperSubstantial claim - Findingown data
Extracts from cells expressing R172K mutant IDH2 did not display isocitrate-dependent NADPH production above vector-transfected cells.
“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”
Quote in the paperSubstantial claim - Findingown data
None of the samples with a 2HG/glutamate signal ratio ≤1% had an IDH mutation.
“none of the samples with a 2HG/glutamate signal ratio ≤ 1% had an IDH mutation”
Quote in the paperSubstantial claim - Findingown data
IDH2 R172K expressing cells had an approximately 100-fold increase in intracellular 2HG compared with vector-transfected and IDH2 wild-type overexpressing cells.
“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”
Quote in the paperSubstantial claim - Findingown data
The R140Q mutant IDH2 is predicted to maintain its ability to bind and orient α-ketoglutarate in the active site despite reduced isocitrate binding.
“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”
Quote in the paperSubstantial claim - Findingown data
AML patients with IDH mutations have a significantly reduced number of other well-characterized AML-associated mutations and/or chromosomal abnormalities.
“AML patients with IDH mutations display a significantly reduced number of other well characterized AML-associated mutations and/or associated chromosomal abnormalities”
Quote in the paperSubstantial claim - Findingown data
IDH1 mutations did not appear to affect overall survival (p=0.37).
“mutations in IDH1 did not appear to affect overall survival (p=0.37, Figure S2A)”
Quote in the paperNot a substantial claim - Findingown data
An IDH2 R172K mutation was found in an AML sample from a 77-year-old female.
“we found an IDH2 R172K mutation in an AML sample obtained from a 77 year old female”
Quote in the paperSubstantial claim - Findingown data
Known cytogenetic abnormalities were observed in 7/51 samples without IDH1/2 mutations (13.7%; p<0.05).
“known cytogenetic abnormalities were observed in 7/51 samples without IDH1/2 mutations (13.7%; all IDH mutants vs. IDH wild-type, p<0.05)”
Quote in the paperNot a substantial claim - Findingown data
IDH2 R172K expression results in elevated 2HG levels.
“Mutation of IDH2 R172K results in elevated 2HG levels”
Quote in the paperSubstantial claim - Findingown data
The remaining AML cases with elevated 2HG had mutations in IDH2.
“The remaining cases with elevated 2HG had mutations in IDH2”
Quote in the paperSubstantial claim - Findingown data
Fewer than half of the AML cases with elevated 2HG carried IDH1 mutations.
“less than half of cases with elevated 2HG possessed IDH1 mutations”
Quote in the paperSubstantial claim - Findingown data
Tumor 2HG levels are elevated in a high proportion of patients with cytogenetically normal acute myeloid leukemia.
“tumor 2HG is elevated in a high percentage of patients with cytogenetically normal acute myeloid leukemia”
Quote in the paperSubstantial claim - Findingown data
IDH2 knockdown did not change citrate +4 levels.
“no change in citrate +4 levels was observed”
Quote in the paperSubstantial claim - Findingown data
siRNA knockdown of either IDH1 or IDH2 significantly reduces the proliferative capacity of a cancer cell line expressing both wild-type IDH1 and IDH2.
“siRNA knockdown of either IDH1 or IDH2 can significantly reduce the proliferative capacity of a cancer cell line expressing both wild-type IDH1 and IDH2”
Quote in the paperSubstantial claim - Findingown data
All five IDH2 mutations producing 2HG in the sample set contained the same mutation, R140Q.
“All five of the IDH2 mutations producing 2HG in this sample set contained the same mutation, R140Q”
Quote in the paperNot a substantial claim - Findingnone given
Both IDH1 and IDH2 mutant proteins cause more than a 100-fold increase in tumor 2HG accumulation.
“Nevertheless, both mutant proteins lead to an over 100-fold increase in tumor 2HG accumulation.”
Quote in the paperSubstantial claim - Findingown data
Samples containing IDH2 R140Q mutations accumulated 2HG to levels 10-100 fold greater than the highest levels detected in IDH wild-type samples.
“samples containing IDH2 R140Q mutations were found to have accumulated 2HG to levels 10–100 fold greater than the highest levels detected in IDH wild-type samples”
Quote in the paperSubstantial claim - Findingown data
Control extracts had either undetectable 2HG or a 2HG signal of at most 1% of that for glutamate (n=13, p<0.001).
“control extracts have either had undetectable 2HG or a 2HG signal ≤ 1% of that for glutamate (n=13, p<0.001)”
Quote in the paperSubstantial claim - Findingown data
IDH1 R132 and IDH2 R172 are analogous residues that both interact with the β-carboxyl of isocitrate.
“IDH1 R132 and IDH2 R172 are analogous residues that both interact with the β-carboxyl of isocitrate”
Quote in the paperSubstantial claim - Findingown data
Leukemic cells bearing either IDH1 R132H or IDH2 R172K mutations accumulate 2HG.
“Leukemic cells bearing heterozygous R172K IDH2 mutations accumulate 2HG”
- Also stated in: § Leukemic cells bearing heterozygous R172K IDH2 mutations accumulate 2HG · boosted
“every IDH1 R132H or IDH2 R172K mutant AML sample has exhibited evidence of 2HG accumulation”
Quote in the paperSubstantial claim - Also stated in: § Leukemic cells bearing heterozygous R172K IDH2 mutations accumulate 2HG · boosted
- Findingown data
Several AML DNA samples were found to have IDH2 R172 mutations.
“Several cases with IDH2 R172 mutations were identified”
Quote in the paperSubstantial claim - Findingown data
R172K mutant IDH2 expression correlates with a significant enhancement of α-ketoglutarate-dependent NADPH consumption.
“R172K mutant IDH2 expression was found to correlate with a significant enhancement to α-ketoglutarate-dependent NADPH consumption”
Quote in the paperSubstantial claim - Findingnone given
2HG levels in cancers with IDH mutations are consistently 10-100 fold elevated over levels found in samples lacking mutations of IDH1 or IDH2.
“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”
Quote in the paperSubstantial claim - Findingown data
Wild-type IDH2 overexpression also reproducibly enhanced α-ketoglutarate-dependent NADPH consumption.
“wild-type IDH2 overexpression also reproducibly enhanced α-ketoglutarate-dependent NADPH consumption under these conditions”
Quote in the paperNot a substantial claim - Findingown data
Every IDH1 R132H or IDH2 R172K mutant AML sample exhibited a 2HG signal intensity of at least 30% of the intrasample glutamate signal.
“every IDH1 R132H or IDH2 R172K mutant AML sample has exhibited evidence of 2HG accumulation, demonstrating a 2HG signal intensity by GC-MS analysis that is ≥ 30% of the intrasample glutamate signal”
Quote in the paperSubstantial claim - Findingown data
The initial IDH2 mutation found, R172K, was the same mutation reported in glioma samples.
“In the initial case, the IDH2 mutation found, R172K, was the same mutation reported in glioma samples”
Quote in the paperSubstantial claim - Findingown data
IDH2 and IDH1 mutations were only observed in normal karyotype AML patients.
“IDH2 and IDH1 mutations were only observed in normal karyotype AML patients”
Quote in the paperNot a substantial claim - Findingown data
Mutant IDH2 produces the (R) enantiomer of 2HG.
“Mutant IDH2 produces the (R) enantiomer of 2HG”
Quote in the paperSubstantial claim - Findingown data
Extracts from cells expressing wild-type IDH2 markedly increased isocitrate-dependent NADPH production.
“extracts from cells expressing a comparable amount of wild-type IDH2 markedly increased isocitrate-dependent NADPH production”
Quote in the paperNot a substantial claim - Findingown data
IDH1-mutated and IDH2-mutated AML samples typically do not harbor other known mutations associated with AML.
“This is consistent with data presented here that IDH1-mutated and IDH2-mutated AML samples typically do not harbor other known mutations associated with AML, as well as a prior report that IDH-mutated gliomas often lack other mutations that are commonly acquired early in glioma pathogenesis (Yan et al., 2009).”
Quote in the paperNot a substantial claim - Findingown data
IDH mutations occur in 23% of samples analyzed here.
“Taken together, IDH mutations occur in 23% of samples analyzed here.”
- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
“Overall, IDH1 and IDH2 mutations were observed in over 23% of AML patients.”
Quote in the paperNot a substantial claim - Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
- Findingown data
The product of the neomorphic enzyme activity can be readily detected in tumor samples.
“The product of this neomorphic enzyme activity can be readily detected in tumor samples and we show that tumor metabolite analysis can identify patients with tumor-associated IDH mutations.”
Quote in the paperSubstantial claim - Findingnone given
To date, there is no evidence that 2HG acts as a mutagen.
“Although 2HG has been proposed to increase ROS levels in patients with inborn errors of 2HG metabolism (Kolker et al., 2002b; Latini et al., 2003), to date we have no evidence that the metabolite acts as a mutagen.”
Quote in the paperNot a substantial claim - Findingown data
Tumor metabolite analysis can identify patients with tumor-associated IDH mutations.
“The product of this neomorphic enzyme activity can be readily detected in tumor samples and we show that tumor metabolite analysis can identify patients with tumor-associated IDH mutations.”
Quote in the paperSubstantial claim - Findingown data
IDH2 R140Q mutations occur in 9% of AML cases.
“Using this method, we discovered a 2HG-producing IDH2 mutation, IDH2 R140Q, that was present in 9% of serial AML samples.”
- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
“IDH2 R140Q mutations occur in 9% of AML cases.”
Quote in the paperNot a substantial claim - Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
- Interpretationreasoning
The common feature linking all cancer-associated IDH mutations is the truncated, non-carboxylating reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate.
“it is the truncated, non-carboxylating, reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate that is the common feature linking all cancer-associated IDH mutations”
Quote in the paperSubstantial claim - Interpretationown data
IDH mutation may implicate a distinct mechanism of AML pathogenesis.
“potentially implicating IDH mutation in a distinct mechanism of AML pathogenesis”
Quote in the paperSubstantial claim - Interpretationown data
The lack of reduction to homozygosity for IDH2 mutations in cancer may be explained by a role for wild-type IDH2 in reductive carboxylation.
“provide a possible explanation for the lack of reduction to homozygosity for IDH2 mutations in cancer”
Quote in the paperSubstantial claim- Rests on an assumption: All reported IDH1 or IDH2 mutations are heterozygous, with cancer cells retaining one wild-type copy of the relevant allele.
- Interpretationreasoning
Tumors displaying elevated 2HG are unlikely to be false positives.
“Tumors displaying elevated 2HG are unlikely to be false positives”
Quote in the paperSubstantial claim - Premisecitation
IDH1 R132 and IDH2 R172 mutants lack the wild-type enzyme's ability to convert isocitrate to α-ketoglutarate.
“Both IDH1 R132 and IDH2 R172 mutants lack the wild-type enzyme’s ability to convert isocitrate to α-ketoglutarate”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yan et al., 2009 source
Not checked in the free run.
- Interpretationown data
Both IDH1 and IDH2 mutations can occur in AML.
“This finding confirmed that both IDH1 and IDH2 mutations can occur in AML”
Quote in the paperSubstantial claim - Interpretationown data
2HG measurement was predictive of IDH mutation status in the 18-sample set.
“Thus in this sample set, 2HG measurement was predictive of IDH mutation status”
Quote in the paperSubstantial claim - Interpretationreasoning
A shared feature of all cancer-associated IDH mutations is the production of the onco-metabolite 2HG.
“a shared feature of all cancer-associated IDH mutations is production of the onco-metabolite 2HG”
Quote in the paperSubstantial claim - Interpretationreasoning
The roles of IDH1 and IDH2 in supporting cell proliferation are likely different.
“The roles of IDH1 and IDH2 in supporting cell proliferation are likely to be different.”
Quote in the paperNot a substantial claim - Interpretationreasoning
2HG appears to be an important marker of IDH1/2-mutated neoplasms.
“Thus, 2HG appears to be an important marker of IDH1/2-mutated neoplasms”
Quote in the paperSubstantial claim - Interpretationown data
2HG production is a common feature of the spontaneous mutations in IDH1 and IDH2.
“we have demonstrated that 2HG production is a common feature of the spontaneous mutations in these two IDH homologs”
Quote in the paperSubstantial claim - Interpretationreasoning
These data argue against IDH mutations resulting in a simple loss of function.
“These data argue against the IDH mutations resulting in a simple loss of function”
Quote in the paperSubstantial claim- Rests on an assumption: All reported IDH1 or IDH2 mutations are heterozygous, with cancer cells retaining one wild-type copy of the relevant allele.
- Rests on an assumption: No patient has been reported with both an IDH1 and IDH2 mutation.
- Premisecitation
2HG is elevated in IDH1-mutated gliomas.
“2HG was found to be elevated in IDH1-mutated gliomas”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dang et al., 2009 source
Not checked in the free run.
- Premisecitation
IDH-mutated gliomas often lack other mutations commonly acquired early in glioma pathogenesis.
“This is consistent with data presented here that IDH1-mutated and IDH2-mutated AML samples typically do not harbor other known mutations associated with AML, as well as a prior report that IDH-mutated gliomas often lack other mutations that are commonly acquired early in glioma pathogenesis (Yan et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yan et al., 2009 source
Not checked in the free run.
- Interpretationreasoning
2HG appears to represent a highly correlative marker for an emerging class of somatic mutations in isocitrate dehydrogenase enzymes.
“For now, it appears to represent a highly correlative maker for an emerging class of somatic mutations in the isocitrate dehydrogenase enzymes.”
Quote in the paperSubstantial claim - Interpretationown data
Finding frequent IDH2 mutations in AML raises the importance of this mutation family for understanding AML pathogenesis.
“The identification of frequent IDH2 mutations in AML increases the significance of this family of mutations in understanding the pathogenesis of AML.”
Quote in the paperSubstantial claim - Premisecitation
In an AML case with an IDH1 mutation sequenced in its entirety, there were a relatively small total number of somatic, non-synonymous mutations.
“In an AML case with an IDH1 mutation that was sequenced in its entirety (Mardis et al., 2009), there were a relatively small total number of somatic, non-synonymous mutations.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mardis et al., 2009 source
Not checked in the free run.
- Premisecitation
A local supply of NADPH and α-ketoglutarate is required to drive 2HG production by IDH1 mutant proteins.
“In the case of IDH1 mutant proteins, it has been reported that a local supply of NADPH and α-ketoglutarate is required to drive 2HG production (Dang et al., 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dang et al., 2009 source
Not checked in the free run.
- Interpretationnone given
These mutations appear to define a significant subset of CNS tumors and leukemias.
“Importantly, these mutations appear to define a significant subset of CNS tumors and leukemias.”
Quote in the paperSubstantial claim- Rests on an assumption: IDH mutations occur frequently in gliomas with mixed astrocytic and oligodendroglial features and in acute myeloid leukemias.
- Interpretationreasoning
For mitochondrial IDH2 mutants, the requirement for local substrate generation is unlikely to be absolute.
“However, for the neomorphic activity of mitochondrial IDH2 mutants, the requirement for local generation of substrate is unlikely to be absolute.”
Quote in the paperNot a substantial claim- Rests on an assumption: Mitochondrial α-ketoglutarate levels are kept high by various anaplerotic substrates.
- Interpretationreasoning
In a wild-type/mutant IDH1 heterodimer, the mutant's neomorphic activity substrates are most readily provided by the wild-type subunit's normal activity on NADP+ and isocitrate.
“In the context of a wild-type/mutant IDH1 heterodimer, the required substrates for the mutant’s neomorphic activity are most readily provided by the wild-type subunit’s normal activity on NADP+ and isocitrate.”
Quote in the paperSubstantial claim- Rests on an assumption: IDH1 contributes to cytosolic NADPH production.
- May combine two claims. 10
- Classified as probably not a substantial claim. 17
May combine two claims.
Findingnone givenBoth wild-type IDH1 and IDH2 play positive and non-redundant roles in cell proliferation.
“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.”
Quote in the paperNot a substantial claim- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
May combine two claims.
Findingown dataIDH1 mutations were found in 7.7% (6/78) and IDH2 mutations in 15.4% (12/78, p<0.05) of serial AML samples.
“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)”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Findingnone givenIDH2 mutations are more common than IDH1 mutations in AML.
“IDH2 mutations are more common than IDH1 mutations in AML”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIDH3 siRNA treatment caused a reproducible increase in citrate +5, while citrate +4 was unchanged.
“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”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Findingnone givenOverall, IDH2 mutations appear more common than IDH1 mutations in AML.
“Overall, IDH2 mutations appear more common than IDH1 mutations in AML.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIDH1 mutations occur somatically in more than 70% of grade II-III gliomas and secondary glioblastomas, and in 8.5% of acute myeloid leukemias.
“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)”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationIDH1 R132 mutations were observed in 8.5% of AML patients studied, with a significantly higher percentage in the subset lacking cytogenetic abnormalities.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mardis et al., 2009 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationCancer-associated IDH1 R132 mutants display a loss-of-function for isocitrate as substrate and a concomitant gain-of-function for the reduction of α-ketoglutarate to 2HG.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dang et al., 2009 source
Not checked in the free run.
May combine two claims.
Interpretationown dataThese data support a role for IDH2 and not IDH3 in the conversion of α-ketoglutarate into citrate by reductive carboxylation in the mitochondria.
“These data support a role for IDH2 and not IDH3 in the conversion of α-ketoglutarate into citrate by reductive carboxylation in the mitochondria”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationThe R132H IDH1 mutation observed in gliomas displays a gain of function for the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate.
“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)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dang et al., 2009 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataCitrate was detected on two different LC-MS approaches that gave comparable results.
“After redissolving samples in deionized water, citrate was detected on two different LC-MS approaches, both of which gave comparable results.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone givenHuman IDH2 has 97% homology with pig IDH2, and none of the 13 differing residues are in the active site.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe requirement for wild-type IDH2 in supporting cell growth correlates with IDH2's ability to contribute to conversion of α-ketoglutarate into citrate via reductive carboxylation in mitochondria of proliferating cells.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataIn enzymatic assays, OD340 changes in assay buffer lacking lysate protein were subtracted from lysate measurements.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenActin antibody was used to assess equal protein loading of Western blots.
“Actin antibody (Santa Cruz, sc1616) was also used to assess equal protein loading of Western blots.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationIsotopomer distributions were corrected for naturally occurring heavy isotopes using a correction matrix.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Weckwerth, 2007
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe 2HG metabolite peak was identified using standards from Sigma.
“Identification of the 2HG metabolite peak was confirmed using standards obtained from Sigma.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA PDB structure of pig IDH2 with isocitrate in the active site is available (1LWD).
“A PDB structure of pig IDH2 is available, with isocitrate in the active site (1LWD) (Ceccarelli et al., 2002).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ceccarelli et al., 2002 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFor samples with less than 70% blasts, flow cytometric sorting was used to isolate blast cells before DNA isolation.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataWild-type and mutant sequences were confirmed by direct sequencing before expression in mammalian cells.
“Wild-type and mutant sequences were then subcloned into pcDNA3 (Invitrogen) and confirmed by direct sequencing before expression in mammalian cells.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenDNA samples were whole genome amplified and mutations were validated on unamplified DNA to ensure mutations were present in the diagnostic sample.
“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.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningAll mutations were validated by repeat PCR and sequencing on unamplified DNA from the archival sample.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMitochondria typically have a high NADPH/NADP+ ratio, supported in part by interconversion of NADPH and NADH in the matrix.
“Mitochondria typically have a high NADPH/NADP+ ratio, supported in part by the ability to interconvert NADPH and NADH in the matrix (Rydstrom, 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rydstrom, 2006 source
Not checked in the free run.
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?
Wild-type IDH1 and IDH2 catalyze the reversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate and CO2; cancer-associated mutations eliminate this function and confer a neomorphic activity generating D-2-hydroxyglutarate via reduction of alpha-ketoglutarate.
“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
Various tumors, including glioma, secondary glioblastoma, and acute myeloid leukemia, harboring heterozygous point mutations in the active sites of IDH1/2 show dramatic increases in R-2-HG levels.
“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]
The high R-2HG concentrations observed in malignant brain tumours and leukaemias, more than 10 mM, might be sufficient to inhibit even the less-susceptible 2OG oxygenases.
“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
Production of 2HG by IDH mutations is stereospecific.
“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
IDH mutations also cause a gain of function that converts 2OG to R-2HG.
“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
Tumor-associated IDH mutations enable production of R-2-hydroxyglutarate, which accumulates to low millimolar levels in IDH mutant tumors.
“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
Oncogenic mutations in genes encoding IDH1/2 result in neomorphic enzyme activity that favors reduction of αKG to d-2-hydroxyglutarate (D-2HG).
“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]
Mutant IDH1 and IDH2 exhibit neomorphic function converting α-ketoglutarate to D-2-hydroxyglutarate.
“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
2-HG acts as a competitive inhibitor of α-KG, and its production by mutant IDH1 consumes α-KG, leading to reduced TET2 and JmjC activity in tumor cells.
“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]
The common feature of the remaining subset of 2HG-elevated AMLs is another mutation in IDH2 at R140.
“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
IDH2 R172 mutations result in 2HG elevation in primary AML samples.
“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
Some 2HG-elevated AML samples lack IDH1 R132 or IDH2 R172 mutations.
“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
IDH-dependent reductive carboxylation has been investigated as a way to produce citrate and fatty acids from α-ketoglutarate derived from glutamine.
“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
R(-)-2HG (D-2HG) is the exclusive 2HG stereoisomer produced by IDH1 and IDH2 mutants.
“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.”
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“To determine the chirality of the 2HG produced by mutant IDH2 and to compare it with that produced by R132H mutant IDH1, we used a two-step derivatization method to distinguish the stereoisomers of 2HG by GC-MS: an esterification step with R-( )-2-butanolic HCl, followed by acetylation of the 2-hydroxyl with acetic an…”
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Background
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BackgroundR-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling
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BackgroundReversing DNA Methylation: Mechanisms, Genomics, and Biological Functions
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“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
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Glutaminolysis: A Hallmark of Cancer Metabolism
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BackgroundTargeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation
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“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
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“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
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Metabolic Regulation of Epigenetics
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“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).”
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Self-citationMetabolomics in cancer research and emerging applications in clinical oncology
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BackgroundIDH mutation in glioma: molecular mechanisms and potential therapeutic targets
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“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
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Self-citationTracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells
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BackgroundIsocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia
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“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
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What a difference a hydroxyl makes: mutant IDH, (<i>R</i>)-2-hydroxyglutarate, and cancer
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“(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).”
BackgroundPaediatric and adult glioblastoma: multiform (epi)genomic culprits emerge
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“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
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“Chiral derivatization was performed to allow separation of 2HG enantiomers by GC-MS.”
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Self-citationEpigenetic Therapies for Cancer
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“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
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“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
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“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
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“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
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“…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
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Self-citationMYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis
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- 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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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