Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation
Open accessAbstract
Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2-hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of-function mutations were associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem/progenitor cell marker expression, suggesting a shared proleukemogenic effect.
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2-hydroxyglutarate interferes with iron-dependent hydroxylases, including the TET family of 5-methylcytosine hydroxylases.
“Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7.”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [4]
The Results section (page unavailable) identifies TET enzymes as iron-dependent 5-methylcytosine hydroxylases and shows that mutant IDH inhibits TET2-mediated hydroxylation. The paper proposes 2-HG as the mechanism, but does not establish interference with the TET family as a whole or with other iron-dependent hydroxylases; the Discussion treats effects on other enzyme families as a possibility for future study. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIncreased levels of 2-HG may enable a switch to an entirely HIF-independent mechanism.
“Therefore, it is plausible that increased levels of 2-HG may enable a switch to an entirely HIF-independent mechanism.”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [153]
The Introduction proposes that increased 2-HG may interfere with αKG-dependent enzymes such as TET2, and the Results report inhibition of TET2-associated DNA demethylation. These passages support a possible alternative mechanism, but the paper does not describe a switch from a HIF-dependent mechanism or establish that the mechanism is entirely HIF-independent (searched for HIF). Page numbers were not available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredTET2-mutant immature and myeloid cells present with hypermethylation of active enhancers and perturbed TF activity.
“Consistently, TET2-mutant immature and myeloid cells present with hypermethylation of active enhancers and perturbed TF activity (28, 32, 53).”
From PU.1-Dependent Enhancer Inhibition Separates <i>Tet2</i> -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [53]
The Results section on TET2-mutant AMLs reports promoter hypermethylation, supporting the general hypermethylation finding, but it does not identify active enhancers as the affected sites. The Results discussion of transcription-factor binding sites suggests perturbed transcription-factor function in IDH1/2-mutant AMLs, not specifically in TET2-mutant cells. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMutant IDH protein generates the oncometabolite 2-hydroxyglutarate.
“Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7.”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [4]
D-2HG accumulation in cancer cells expressing mutant IDH results in hypermethylation of histones and CpG islands in DNA.
“As a result, D-2HG accumulation in cancer cells expressing mutant IDH results in hypermethylation of histones and CpG islands in DNA (Figueroa et al., 2010; Lu et al., 2012; Turcan et al., 2012).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Figueroa et al., 2010
IDH1 and IDH2 mutations generate D-2HG, which inhibits epigenetic enzymes including histone demethylases and TET family hydroxylases.
“Mutations in isocitrate dehydrogenase isoform-1 (IDH1) and IDH2 generate the oncometabolite D-2-hydroxyglutarate (D-2HG), which inhibits epigenetic enzymes including histone demethylases and the Ten-eleven translocation (TET) family of 5-methylcytosine hydroxylases.”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [25]
These effects contribute to tumor initiation in AML by causing persistent histone and DNA methylation and impaired cellular differentiation.
“These effects contribute to tumor initiation in acute myelogenous leukemia (AML) by resulting in persistent histone and DNA methylation and impaired cellular differentiation (25).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [25]
R-2-HG inhibits α-KG-dependent dioxygenases and demethylases.
“The role of R-2-HG as an oncometabolite has been implicated in epigenetic modifications through the inhibition of α-KG-dependent dioxygenases and demethylases”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [117]
TET2 inactivation is sufficient to promote hematopoietic stem cell self-renewal and block differentiation.
“In addition, TET2 inactivation is sufficient to promote hematopoietic stem cell self-renewal and to block differentiation (Figueroa et al., 2010; Li et al., 2011; Moran-Crusio et al., 2011; Noushmehr et al., 2010; Turcan et al., 2012; Losman et al., 2013).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Figueroa et al., 2010
TET2 and IDH mutations are both found in AML and are mutually exclusive, consistent with R-2HG from mutant IDH providing an alternative way to inactivate TET2.
“In this regard, TET2 and IDH mutations are both found in acute myelogenous leukemia and are mutually exclusive, consistent with the idea that R-2HG produced by mutant IDH provides an alterative means of inactivating TET2 (Figueroa et al., 2010).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Figueroa et al., 2010
R-2HG, succinate, and fumarate can inhibit multiple 2-oxoglutarate-dependent dioxygenases, including JmjC histone demethylases and TET proteins, at sufficiently high concentrations.
“R-2HG, succinate, and fumarate are all capable of inhibiting multiple 2-oxoglutarate-dependent dioxygenases, including the JmjC histone demethylases and TET proteins, when present at sufficiently high concentrations (Figure 6B) (Cervera et al., 2009; Chowdhury et al., 2011; Figueroa et al., 2010; Koivunen et al., 2012; Lu et al., 2012; Smith et al., 2007; Turcan et al., 2012; Xiao et al., 2012; Xu”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Figueroa et al., 2010
The catalytic activity of EZH2 can be compromised by so-called 'oncohistones'.
“More recently, we have also learnt how the catalytic activity of EZH2 can be compromised by so called 'oncohistones' 100 (Figure 3).”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [100]
Around 30% of all paediatric glioblastomas contain mutations in histone genes resulting in H3K27M, H3K27I and H3G34V/R substitutions.
“Around 30% of all paediatric glioblastomas contain mutations in histone genes resulting in H3K27M, H3K27I and H3G34V/R substitutions (reviewed in REF. 100 ).”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [100]
A large AML cohort showed that TET2 mutations and gain-of-function IDH1/IDH2 mutations did not co-occur.
“in a large acute myelogenous leukaemia (AML) cohort, TET2 was found to be mutually exclusive with gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 (REF.65).”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [65]
Heterozygous, inactivating TET2 mutations and neomorphic IDH mutations are recurrent and mutually exclusive in acute myeloid leukaemia genomes.
“Heterozygous, inactivating ten-eleven translocation 2 (TET2) mutations and neomorphic isocitrate dehydrogenase (IDH) mutations are recurrent and mutually exclusive in acute myeloid leukaemia genomes.”
From Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia (2018) · cites this paper as [5]
By blocking the enzymatic activity of histone and DNA demethylases, d-2HG can lock cells in a hypermethylated state that blocks differentiation and reinforces a malignant and stem cell-like phenotype.
“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, 173, 174).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [172]
IDH-driven gliomas, leukemias, and chondrosarcomas display prominent CpG island hypermethylation reminiscent of SDH- and FH-deficient cancers.
“Indeed, IDH-driven gliomas, leukemias and chondrosarcomas display a prominent CpG island hypermethylation, reminiscent of the hypermethylator phenotype seen in SDH- and FH-deficient cancers (Figueroa et al., 2010; Lu et al., 2013; Turcan et al., 2012).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Figueroa et al., 2010
IDH mutations in AML are mutually exclusive with inactivating TET2 mutations, implicating mutant IDH as driver of epigenetic remodeling.
“IDH mutations in AML are mutually exclusive with inactivating mutations in TET2 methylcytosine hydroxylases, further implicating mutant IDH as a bona fide driver of epigenetic remodeling (Figueroa et al., 2010).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Figueroa et al., 2010
In the cancer setting, 2-HG influences a number of biological processes, including cell differentiation, DNA methylation, and histone methylation.
“In the cancer setting, 2-HG has been shown to influence a number of biological processes, including cell differentiation, DNA methylation, and histone methylation (79–82), leading to its classification as an oncometabolite.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [79]
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 [79]
Mutant IDH2 [Arg140→Gln140 (R140Q)] promotes α-KG depletion/2-HG production, promotes DNA hypermethylation in hematopoietic cells, and can inhibit myeloid differentiation when overexpressed in bone marrow stem cells.
“Mutant IDH2 [Arg140→Gln140 (R140Q)], which promotes α-KG depletion/2-HG production, promotes DNA hypermethylation in hematopoietic cells and can inhibit myeloid differentiation when overexpressed in bone marrow stem cells (79).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [79]
IDH mutant expression and 2HG elevation can inhibit the TET family of enzymes that hydroxylate 5'-methylcytosine.
“multiple groups have found that IDH mutant expression and 2HG elevation can inhibit the TET family of enzymes that hydroxylate 5’-methylcytosine (Figueroa et al., 2010; Turcan et al., 2012; Xu et al., 2011)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Figueroa et al., 2010
TET2 mutant AML samples display an overlapping DNA hypermethylation signature with samples having IDH1 or IDH2 mutations.
“TET2 mutant AML samples displayed an overlapping DNA hypermethylation signature with samples having IDH1 or IDH2 mutations”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Figueroa et al., 2010
Neomorphic mutations of IDH1 or IDH2 and TET2 loss-of-function mutations are mutually exclusive in a large AML cohort.
“neomorphic mutations of IDH1 or IDH2 and TET2 loss-of-function mutations were found to be mutually exclusive in a large AML cohort”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Figueroa et al., 2010
Overexpression of IDH mutants blocks acquisition of mature myeloid markers while increasing expression of stem cell markers in 32D myeloid cells and mouse primary bone marrow cells cultured ex vivo.
“In both cell types, the overexpression of IDH mutants blocked acquisition of mature myeloid markers while increasing the expression of stem cell markers (Figueroa et al., 2010).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Figueroa et al., 2010
shRNA knockdown of TET2 recapitulates the effect of IDH mutant overexpression on blocking hematopoietic cell differentiation.
“shRNA knockdown of TET2 recapitulated the effect of IDH mutant overexpression on blocking hematopoietic cell differentiation (Figueroa et al., 2010)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Figueroa et al., 2010
Mutations in IDH1/2 and in the 5-methylcytosine hydroxylase TET2 occur frequently in acute myelogenous leukemia.
“mutations in IDH1/2 and in the 5-methylcytosine hydroxylase TET2 occur frequently in acute myelogenous leukemia”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Figueroa et al., 2010
Primary IDH1- or IDH2-mutant tumors showed evidence of extensively altered histone and DNA methylation in vivo.
“primary IDH1- or IDH2-mutant tumors showed evidence of extensively altered histone and DNA methylation in vivo”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Figueroa et al., 2010
IDH1/2 and TET2 mutations were found to be mutually exclusive in acute myelogenous leukemia.
“the mutations were found to be mutually exclusive”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Figueroa et al., 2010
High concentrations of 2-HG inhibited the function of α-ketoglutarate-dependent histone demethylases and 5-methylcytosine hydroxylases in vitro.
“high concentrations of 2-HG inhibited the function of α-ketoglutarate-dependent histone demethylases and 5-methylcytosine hydroxylases in vitro”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Figueroa et al., 2010
Metabolomic profiling of mIDH1/2 gliomas revealed significant alterations in cellular metabolism, recapitulated by exogenous D-2-HG.
“metabolomic profiling of mIDH1/2 gliomas revealed significant alterations in cellular metabolism, an effect recapitulated with the exogenous addition of D-2-HG134.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [134]
D-2-HG-induced metabolic rewiring decreases NAAG, and NAAG levels are significantly lower in IDH-mutant human glioma tissue.
“This metabolic rewiring resulted in a decrease in a common dipeptide found in the brain N-acetyl-aspartyl-glutamate (NAAG), and NAAG levels were found to be significantly lower in IDH-mutant human glioma tissue134.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [134]
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“Because IDH mutants block cell differentiation and promote tumor transformation, and inhibition of mutant IDH (IDHi) can reverse this effect, R-2HG (as the major metabolic product of IDH mutants) has been regarded as an oncometabolite (Figueroa et al., 2010; Lu et al., 2012; Rohle et al., 2013;Wang et al., 2013; Xu et…”
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- Authors
- Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., Tallman, M. S., Sun, Z., Wolniak, K., Peeters, J. K., Liu, W., Choe, S. E., Fantin, V. R., Paietta, E., Löwenberg, B., Licht, J. D., Godley, L. A., Delwel, R., Valk, P. J. M., Thompson, C. B., Levine, R. L., & Melnick, A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Abramson Cancer Center (US)
- Weill Cornell Medicine (US)
- University of Chicago (US)
- Moffitt Cancer Center (US)
- Harvard University (US)
- Northwestern University (US)
- Erasmus MC (NL)
- Agios Pharmaceuticals (United States) (US)
- Montefiore Medical Center (US)
- Corresponding author
- Thompson, Craig B.
- Levine, Ross L.
- Melnick, Ari
- ORCID
- Abdel-Wahab, Omar
- Ward, Patrick S.
- Patel, Jay
- Shih, Alan
- Li, Yushan
- Bhagwat, Neha
- Vasanthakumar, Aparna
- Fernandez, Hugo F.
- Tallman, Martin S.
- Sun, Zhuoxin
- Wolniak, Kristy
- Liu, Wei
- Choe, Sung E.
- Fantin, Valeria R.
- Paietta, Elisabeth
- Löwenberg, Bob
- Licht, Jonathan D.
- Godley, Lucy A.
- Delwel, Ruud
- Valk, Peter J.M.
- Thompson, Craig B.
- Levine, Ross L.
- Melnick, Ari
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 18
- Issue
- 6
- Pages
- 553-567
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4105845
- OpenAlex
- W2078972833
- Cited by
- 2,766
- References
- 35
- Citations by year
- 2026: 92 · 2025: 114 · 2024: 156 · 2023: 158 · 2022: 155 · 2021: 213 · 2020: 183 · 2019: 165 · 2018: 178 · 2017: 196 · 2016: 186 · 2015: 193 · 2014: 217 · 2013: 214 · 2012: 191
- FWCI
- 111.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- University of Pennsylvania
- Agios Pharmaceuticals
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL082950)
- National Cancer Institute (CA114737, R01CA105463, U54CA143798, U24CA114737, R01CA173636, U10CA021115, CA 21115)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- IDH1 mutation, IDH2 mutation, acute myeloid leukemia, DNA hypermethylation, 2-hydroxyglutarate, TET2, hematopoietic differentiation, epigenetic dysregulation, stem/progenitor cells
- MeSH terms
- MDS1 and EVI1 Complex Locus Protein, Cell Differentiation, DNA-Binding Proteins, Humans, Hydroxylation, Isocitrate Dehydrogenase, Mutation, Phenotype, Proto-Oncogene Proteins, Proto-Oncogenes, Transcription Factors, Leukemia, Myeloid, Acute, DNA Methylation, Myeloid Cells, 5-Methylcytosine, Dioxygenases, GATA1 Transcription Factor, Gene Regulatory Networks
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