Affinage

IDH1

Isocitrate dehydrogenase [NADP] cytoplasmic · UniProt O75874

Length
414 aa
Mass
46.7 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IDH1 is a cytoplasmic NADP+-dependent enzyme whose oncogenic R132 mutations exemplify a gain-of-function neomorphic activity that reprograms cellular metabolism and epigenetics across multiple tumor types (PMID:19935646). The mutant enzyme loses normal isocitrate-to-α-ketoglutarate oxidative decarboxylation and instead reduces α-ketoglutarate to the oncometabolite R(-)-2-hydroxyglutarate (2HG), a reaction enabled by repositioning of active-site residues seen crystallographically (PMID:19935646, PMID:19228619). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, impairing TET2 catalysis and driving genome-wide DNA hypermethylation and histone-mark remodeling sufficient to establish the glioma CpG-island methylator phenotype and a proliferative stem-like state (PMID:21130701, PMID:22343889, PMID:29180699). This epigenetic reprogramming underlies several immune phenotypes: mutant IDH1 silences the cytoplasmic dsDNA sensor CGAS by promoter hypermethylation, suppresses transposable-element-driven viral mimicry (PMID:38991060), dampens baseline innate immune gene expression (PMID:38272925), and impairs type I interferon responses through 2HG-enhanced DNMT1 binding at IRF3/7 promoters (PMID:37880243). Beyond chromatin, 2HG produces metabolic and signaling consequences independent of methylation, including inhibition of OGDH to attenuate succinyl-CoA-dependent heme biosynthesis (PMID:33254233), SCD-driven monounsaturated fatty acid accumulation causing ER and Golgi dilation (PMID:33504762), reduced NADPH and elevated ROS conferring radiosensitivity (PMID:26363012), and binding of Cdc42 to block the MLK3→JNK→Bim apoptotic cascade (PMID:28402860). Continued mutant IDH1 expression is required to maintain tumor growth (PMID:22885298), and mutant-selective allosteric inhibitors exploit a regulatory-segment destabilization unique to mutant IDH1 (PMID:28132785). Wild-type IDH1 retains physiological importance, mediating hypoxic reductive carboxylation of glutamine-derived α-ketoglutarate for lipogenesis (PMID:22101433) and supporting cancer cell survival through anaplerosis and NADPH-dependent antioxidant defense (PMID:38843355); its enzymatic output is regulated by SIRT2-mediated K224 deacetylation (PMID:32141187) and its mRNA stabilized by HuR (PMID:30266754).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2009 High

    Established the central paradox of IDH1 in cancer—that R132 mutations both abolish normal activity and create a neomorphic reaction—which redefined how a metabolic enzyme can act as an oncogene.

    Evidence In vitro enzymatic assays of mutant vs wild-type protein, X-ray crystallography of R132H, and metabolite profiling in glioma cells and tissue

    PMID:19228619 PMID:19935646

    Open questions at the time
    • Did not connect 2HG production to downstream epigenetic or signaling effectors
    • Did not address whether 2HG is necessary for transformation in vivo
  2. 2010 High

    Placed mutant IDH1 upstream of TET2 and DNA methylation, explaining how a metabolic lesion produces an epigenetic phenotype and why IDH and TET2 mutations are mutually exclusive.

    Evidence Mutant allele expression in cells, TET2 catalytic assay, genome-wide methylation profiling, and genetic epistasis in an AML cohort

    PMID:21130701

    Open questions at the time
    • Did not demonstrate sufficiency of the methylation phenotype for tumor initiation
    • Did not resolve which specific dioxygenases dominate the phenotype
  3. 2012 High

    Demonstrated that a single mutant IDH1 allele is sufficient to establish the glioma CIMP and is leukemogenic in vivo, and that mutant expression is continuously required for tumor maintenance.

    Evidence Stable expression in primary astrocytes with methylome profiling, conditional knock-in mouse models with hematopoietic readouts, and inducible shRNA suppression of endogenous mutant in a native heterozygous line

    PMID:22343889 PMID:22763442 PMID:22885298

    Open questions at the time
    • Astrocyte/mouse systems do not fully recapitulate human tumor heterogeneity
    • Did not define cooperating lesions needed for full malignancy
  4. 2011 High

    Revealed that wild-type IDH1 has a distinct physiological role in hypoxic reductive carboxylation for lipogenesis, separating wild-type from mutant function.

    Evidence 13C isotope tracing under normoxia/hypoxia with IDH1 knockdown in multiple human cell lines

    PMID:22101433

    Open questions at the time
    • Did not address how this pathway interacts with mutant alleles in heterozygous cells
    • In vivo relevance of reductive carboxylation not established here
  5. 2017 High

    Defined the structural basis for mutant-selective inhibition, showing R132H destabilizes a regulatory segment to open an allosteric pocket absent in IDH2.

    Evidence X-ray crystallography of R132H with two distinct inhibitor scaffolds, regulatory-segment mutagenesis, and enzymatic inhibition assays

    PMID:28132785

    Open questions at the time
    • Did not address resistance mechanisms to allosteric inhibitors
    • Selectivity in cellular and in vivo contexts not the focus
  6. 2017 Medium

    Showed mutant IDH1 drives coordinate, eventually irreversible epigenomic reprogramming and establishes a stem-like proliferative population, but requires cooperating lesions for gliomagenesis.

    Evidence Inducible mutant expression in astrocytes/tumorspheres with ATAC-seq, ChIP-seq, RNA-seq, methylation profiling and inhibitor reversal; separate in vivo model with PDGFA, Cdkn2a, Atrx, Pten alterations

    PMID:29180699 PMID:29719265

    Open questions at the time
    • Determinants of reversible vs irreversible epigenetic state not fully resolved
    • Precise cooperating-lesion hierarchy not defined
  7. 2015 Medium

    Identified methylation-independent metabolic and redox consequences of 2HG, including PDH suppression and NADPH depletion driving radiosensitivity.

    Evidence Hyperpolarized 13C-MRS, PDH activity assays, ROS and DSB quantification, clonogenic radiation survival with inhibitor and exogenous D-2HG rescue

    PMID:26045167 PMID:26363012

    Open questions at the time
    • Single-lab studies without independent replication
    • Relative contribution of metabolic vs epigenetic effects to tumor phenotype unquantified
  8. 2016 Medium

    Extended the methylation reach of mutant IDH1 to metabolite-transporter and coagulation genes, linking it to altered lactate flux and reduced thrombotic tendency.

    Evidence Hyperpolarized 13C-MRS with SLC16A3/SLC16A1 promoter methylation analysis; platelet aggregation, clotting, F3 promoter methylation and in vivo bleeding-time assays

    PMID:27144334 PMID:27664011

    Open questions at the time
    • Single-lab observations
    • Causal contribution of these axes to clinical phenotypes not established
  9. 2017 Medium

    Uncovered a non-epigenetic survival mechanism in which 2HG binds Cdc42 to block the MLK3→JNK→Bim apoptotic cascade.

    Evidence R132Q knock-in cells, 2HG-Cdc42 binding and MLK3 activity assays, JNK/Bim pathway analysis, and allograft tumor model

    PMID:28402860

    Open questions at the time
    • Single-lab biochemistry without independent confirmation
    • Generalizability beyond serum-starvation context unclear
  10. 2018 Medium

    Identified post-transcriptional and post-translational regulation of IDH1 itself via HuR mRNA stabilization and SIRT2-mediated K224 deacetylation.

    Evidence RIP assays with CRISPR/siRNA HuR suppression and metabolomics; proteomics screen with reciprocal SIRT2 Co-IP, K224 acetyl-mimetic/resistant mutants, enzymatic and in vivo invasion assays

    PMID:30266754 PMID:32141187

    Open questions at the time
    • Single-lab findings
    • Physiological stimuli regulating these modifications not defined
  11. 2021 Medium

    Showed 2HG inhibits OGDH to disrupt succinyl-CoA-dependent heme biosynthesis and drives SCD-dependent MUFA accumulation causing organelle dysmorphia, broadening the metabolic consequences of mutant IDH1.

    Evidence R132H knock-in mice with OGDH assay, succinyl-CoA/5-ALA rescue; lipidomics, EM of ER/Golgi, SCD silencing and D-2HG/oleic acid treatment

    PMID:33254233 PMID:33504762

    Open questions at the time
    • Single-lab mechanistic chains
    • Therapeutic relevance of OGDH/SCD axes untested clinically
  12. 2023 Medium

    Defined IDH1-isoform-specific lipid metabolism vulnerabilities, including a defective reductive carboxylation/NADPH state that creates ACC1 synthetic lethality in mutant AML.

    Evidence Primary AML blast metabolomics, isotope tracing, genetic and pharmacological ACC1 inhibition, lipid-free-diet xenografts and venetoclax combination

    PMID:36355448

    Open questions at the time
    • Single-lab study
    • Clinical translatability of ACC1 targeting not established
  13. 2024 Medium

    Established that mutant IDH1 suppresses innate and antitumor immunity through CGAS promoter methylation/viral mimicry, IRF3/7 silencing, and reversible dampening of innate immune gene expression.

    Evidence DNA methylation and TE-RT/cGAMP assays with mIDH1 inhibitor rescue and in vivo immune readouts; DNMT1 ChIP at IRF3/7 with viral infection models; isogenic IDH1/ATRX cell lines with cytokine profiling and xenograft T-cell infiltration

    PMID:37880243 PMID:38272925 PMID:38991060

    Open questions at the time
    • Convergence of these immune mechanisms in a single tumor not integrated
    • Most evidence from single labs in model systems
  14. 2024 Medium

    Characterized wild-type IDH1 as a chemoresistance factor and a pharmacologically activatable tumor-suppressive node, and defined a clinical resistance mechanism to ivosidenib.

    Evidence PDAC chemotherapy models with IDH1 knockdown/ivosidenib synergy; Scutellarin covalent Cys297 activation with HIF1α degradation in HCC; engineered R132C/D279N double-mutant cells with drug binding and the irreversible inhibitor LY3410738

    PMID:36056177 PMID:38622131 PMID:38843355

    Open questions at the time
    • Single-lab studies
    • Frequency and clinical impact of D279N resistance not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse epigenetic, metabolic, redox, and immune effects of 2HG are quantitatively integrated to determine tumor type-specific phenotypes and therapeutic vulnerability remains unresolved.
  • No unifying model weighting epigenetic vs non-epigenetic 2HG effects
  • Determinants of which dioxygenases/pathways dominate in a given tissue undefined
  • Mechanisms governing reversibility of mutant IDH1 phenotypes incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0016740 transferase activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-4839726 Chromatin organization 3
Partners
CDC42DNMT1ELAVL1SIRT2

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Cancer-associated IDH1 mutations at R132 result in loss of the normal isocitrate-to-α-ketoglutarate oxidative decarboxylation activity and acquisition of a neomorphic NADPH-dependent ability to reduce α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Crystal structure of R132H IDH1 shows active-site residues are repositioned to accommodate this new reaction. In vitro enzymatic assay of mutant vs wild-type IDH1, X-ray crystallography of IDH1 R132H, metabolite profiling of glioma cells Nature High 19935646
2009 IDH1 R132 mutations reduce the enzymatic activity of the encoded protein for the normal isocitrate-to-α-ketoglutarate reaction, demonstrated in cultured glioma cells transfected with normal and mutant IDH1/IDH2 constructs. Enzymatic activity assay in transfected glioma cells The New England journal of medicine High 19228619
2010 Expression of 2HG-producing IDH1 mutant alleles in cells induces global DNA hypermethylation and impairs TET2 catalytic function, placing mutant IDH1 upstream of TET2 in the epigenetic pathway; IDH1/2 mutations are mutually exclusive with TET2 loss-of-function mutations in AML, supporting epistatic equivalence. Expression of mutant IDH alleles in cells, TET2 catalytic activity assay, genome-wide DNA methylation profiling, genetic epistasis analysis in AML cohort Cancer cell High 21130701
2012 Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and remodels the methylome in a fashion mirroring G-CIMP in lower-grade gliomas, establishing that a single IDH1 mutation is sufficient to establish the glioma CpG island methylator phenotype. Stable expression of mutant IDH1 in primary astrocytes, genome-wide DNA methylation profiling, histone mark analysis Nature High 22343889
2011 IDH1 mediates reductive carboxylation of glutamine-derived α-ketoglutarate to isocitrate/citrate for de novo lipid synthesis under hypoxia; this IDH1-dependent reductive pathway is the predominant route for acetyl-CoA production for lipogenesis when oxidative TCA cycle activity is suppressed. 13C isotope tracing (metabolic flux analysis) in human cell lines under normoxia/hypoxia, genetic knockdown of IDH1 Nature High 22101433
2012 Conditional knock-in of IDH1 R132H in murine hematopoietic cells produces increased haematopoietic progenitors, splenomegaly, anaemia, and a hypermethylated histone and DNA methylation signature resembling human IDH1-mutant AML, demonstrating in vivo leukemogenic effects of the mutation. Conditional knock-in mouse model (Vav-KI and LysM-KI), histone and DNA methylation analysis, flow cytometry of haematopoietic compartments Nature High 22763442
2017 Allosteric mutant-IDH1-selective inhibitors bind an allosteric pocket on IDH1 that is only accessible because the R132H oncogenic mutation destabilizes an IDH1 'regulatory segment'; this destabilization is not recapitulated in the analogous IDH2 segment, explaining isoform selectivity. Crystal structures of IDH1 with two structurally distinct inhibitors reveal the plasticity of the allosteric site. X-ray crystallography of IDH1 R132H with inhibitors, mutagenesis of regulatory segment, binding and enzymatic inhibition assays Structure High 28132785
2015 IDH1 mutation reduces pyruvate dehydrogenase (PDH) activity through increased PDH inhibitory phosphorylation and upregulation of pyruvate dehydrogenase kinase-3, leading to MRS-detectable reprogramming of pyruvate metabolism; pharmacological restoration of PDH activity abolishes the clonogenic advantage conferred by IDH1 mutation. Hyperpolarized 13C-MRS, PDH activity assay, immunoblotting, clonogenic assay, dichloroacetate pharmacological rescue, patient-derived neurosphere models Cancer research Medium 26045167
2020 SIRT2 deacetylates IDH1 at lysine 224; deacetylation at K224 promotes IDH1 enzymatic activity and α-KG production, while K224 acetylation suppresses activity. IDH1 acetylation inversely regulates HIF1α-dependent SRC transcription and modulates cellular redox homeostasis; IDH1 hyperacetylation is associated with CRC progression. Proteomics screen, Co-IP/deacetylation assay with SIRT2, acetylation-mimetic/resistant K224 mutants, in vitro enzymatic assay, luciferase reporter, in vitro and in vivo invasion assays EMBO reports Medium 32141187
2015 IDH1 mutation reduces NADPH production capacity and increases reactive oxygen species, leading to higher sensitivity to ionizing radiation; exogenous D-2HG recapitulates this radiosensitization in wild-type cells, and the effect is independent of the DNA hypermethylation phenotype. ROS measurement, DNA double-strand break quantification, clonogenic radiation survival assay in IDH1-heterozygous and wild-type cells, IDH1 R132H inhibitor AGI-5198 rescue experiments, D-2HG exogenous treatment Cancer research Medium 26363012
2012 Selective suppression of endogenous mutant IDH1 expression in HT1080 cells (native IDH1 R132C heterozygous mutation) significantly inhibits cell proliferation and reduces clonogenic potential, demonstrating that continued expression of mutant IDH1 is required for maintaining tumor cell growth. Inducible shRNA knockdown of endogenous mutant IDH1 in native heterozygous cancer cell line, proliferation and clonogenic assays Oncotarget Medium 22885298
2017 2HG produced by IDH1 R132Q mutation binds to Cdc42 and prevents Cdc42 from disrupting MLK3 auto-inhibition, thereby blocking the MLK3→MKK4/7→JNK→Bim apoptotic cascade specifically activated by serum starvation, promoting cell survival; this mechanism was demonstrated to contribute to tumorigenesis in allograft models. IDH1-R132Q knock-in mouse cells, JNK/Bim pathway biochemical analysis, 2HG-Cdc42 binding assay, MLK3 activity assay, allograft tumor model, immunohistochemistry of human glioma Cell reports Medium 28402860
2021 D-2HG produced by mutant IDH1 inhibits oxoglutarate dehydrogenase (OGDH) activity, reducing succinyl-CoA production, which attenuates heme biosynthesis in erythroid cells; succinyl-CoA or 5-ALA supplementation rescues erythropoiesis in IDH1-mutant cells, and heme deficiency leads to impaired heme oxygenase-1 expression and excess ROS accumulation causing erythroid cell death. IDH1 R132H conditional knock-in mice, OGDH activity assay, succinyl-CoA metabolite measurement, heme biosynthesis assay, erythroid differentiation assay, succinyl-CoA/5-ALA rescue experiments Blood High 33254233
2021 Mutant IDH1 drives increased monounsaturated fatty acids (MUFA) and their phospholipids via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, causing ER and Golgi dilation; inhibition of mutant IDH1 or SCD silencing restores organelle morphology, while D-2HG or oleic acid treatment induces organelle defects in IDH1-mutant cells. Lipidomics, electron microscopy of ER/Golgi, SCD siRNA knockdown, IDH1 inhibitor treatment, D-2HG and oleic acid exogenous treatment, cell viability assay Nature communications Medium 33504762
2024 Mutant IDH1 epigenetically silences the cytoplasmic dsDNA sensor CGAS via selective CpG hypermethylation of its promoter; mIDH1 inhibition restores CGAS expression and derepresses transposable elements (TEs), whose reverse-transcriptase-derived dsDNA activates cGAS, triggering viral mimicry and antitumor immunity. DNA methylation analysis, CGAS expression rescue by mIDH1 inhibition, TE-RT activity assay, cGAS pathway activation (cGAMP measurement), in vivo immunological readouts in IDH1-mutant tumor models Science High 38991060
2023 D-2HG produced by mutant IDH1 enhances binding of DNMT1 to IRF3/7 promoters, downregulating IRF3 and IRF7 expression, thereby impairing type I interferon antiviral responses in glioma cells and increasing susceptibility to viral infection. Chromatin immunoprecipitation (ChIP) of DNMT1 at IRF3/7 promoters, IRF3/7 expression analysis, IFN pathway activation assay, in vitro viral infection assay, mouse glioma model with oncolytic virus Nature communications Medium 37880243
2017 Mutant IDH1-dependent epigenomic reprogramming in human astrocytes and glioma tumorspheres establishes genome-wide coordinate changes in histone marks and chromatin states; prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations, and mutant IDH1 establishes a CD24+ proliferative stem-like cell population. Human astrocyte and tumorsphere model systems with inducible mutant IDH1 expression, ATAC-seq, ChIP-seq for multiple histone marks, RNA-seq, DNA methylation profiling, IDH1 inhibitor reversal experiments Nature genetics High 29180699
2016 IDH1 mutation drives promoter hypermethylation of the MCT4-encoding gene SLC16A3 (but via a different mechanism for MCT1/SLC16A1), leading to reduced monocarboxylate transporter expression and decreased hyperpolarized pyruvate-to-lactate flux in IDH1-mutant cells. Hyperpolarized 13C-MRS, qRT-PCR, promoter methylation analysis, cell lysate enzymatic comparison, patient TCGA data correlation Oncotarget Medium 27144334
2023 Mutant IDH1 specifically reduces fatty acid levels and induces a switch to β-oxidation in AML blasts (distinct from mIDH2), depleting NADPH via defective reductive carboxylation not rescued by ivosidenib; targeting ACC1 (acetyl-CoA carboxylase 1) is synthetic lethal with mIDH1 in vitro and in xenograft models. Metabolomics of primary AML blasts and cell lines, isotope tracing, genetic ACC1 knockdown, pharmacological ACC1 inhibition, lipid-free diet xenograft model, combination with venetoclax Cancer discovery Medium 36355448
2017 IDH1 R132H cooperates with PDGFA overexpression and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo; immortal astrocytes expressing IDH1 R132H alone show elevated 2HG, reduced NADPH, and increased proliferation and anchorage-independent growth but do not form gliomas alone. In vitro astrocyte transformation assays (soft agar, proliferation), in vivo mouse glioma model with cooperating genetic alterations, 2HG and NADPH measurement Cell reports Medium 29719265
2024 Scutellarin (Scu) activates wild-type IDH1 by selectively modifying Cys297, promoting active IDH1 dimer formation and increasing α-KG production; elevated α-KG leads to ubiquitination and degradation of HIF1α, inhibiting glycolysis and activating the tumor immune microenvironment in HCC. Proteomic microarray, covalent modification site mapping (Cys297), dimerization assay, α-KG enzymatic assay, HIF1α ubiquitination assay, in vitro and in vivo HCC models Cell death & disease Medium 38622131
2018 HuR (ELAVL1) RNA-binding protein stabilizes both wild-type and mutant IDH1 mRNAs in heterozygous IDH1-mutant cancer cells; genetic suppression of HuR (siRNA or CRISPR) simultaneously downregulates both IDH1 isoforms, reduces 2HG levels, and impairs proliferation and invasion, with cells being especially sensitive to combined HuR-loss and IDH1 inhibitor treatment. Ribonucleoprotein immunoprecipitation (RIP) assay, CRISPR HuR deletion, siRNA knockdown, metabolomics (2HG, pentose phosphate pathway metabolites), proliferation and invasion assays Molecular cancer research Medium 30266754
2022 Acquired resistance to ivosidenib in IDH1 R132C-mutated cholangiocarcinoma occurs via secondary IDH1 D279N mutation; the double-mutant IDH1 R132H/D279N produces 2HG less efficiently but retains ability to produce 2HG and promote cellular transformation in the presence of ivosidenib due to impaired ivosidenib binding. An irreversible IDH1 inhibitor (LY3410738) overcomes this resistance. Generation of double-mutant IDH1 expressing cells, 2HG production assay, cellular transformation assay, ivosidenib and LY3410738 binding/inhibition assays NPJ precision oncology Medium 36056177
2024 IDH1 K93 deacetylation (assessed by mutation at K93) reduces IDH1 enzymatic activity and promotes NETosis (neutrophil extracellular trap formation) in dHL-60 cells; deacetylation of IDH1 and MDH1 was detected in acute liver failure mouse models and was associated with worsened disease progression. Immunoprecipitation to detect acetylation, K93 mutation to mimic deacetylation, NETosis markers (immunofluorescence, western blotting), LPS/D-gal mouse ALF model Cellular & molecular biology letters Low 38172700
2013 D-2HG produced by mutant IDH1 increases neuronal firing rate 4–6-fold in cultured rat cortical neurons, an effect completely blocked by the selective NMDA receptor antagonist AP5, suggesting D-2HG acts as an NMDA receptor agonist mimicking glutamate. Microelectrode array recording of rat cortical neurons, exogenous D-2HG treatment, AP5 (NMDA antagonist) pharmacological rescue Neurology Medium 28404805
2016 D-2HG inhibits platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism; mutant IDH1 gliomas show F3 (tissue factor) gene promoter hypermethylation and reduced tissue factor protein expression, reducing thrombotic tendency. In vitro platelet aggregation assay with D-2HG, clotting time assay, F3 promoter methylation analysis, TF protein IHC, mutant IDH1 glioma mouse engraftment with bleeding time measurement Acta neuropathologica Medium 27664011
2014 Expression of IDH1 R132H mutant in Drosophila hemocytes results in higher numbers of circulating blood cells; neurological and wing-expansion defects from mutant Idh expression are rescued by genetic modulation of superoxide dismutase 2, p53, and apoptotic caspase cascade mediators; coexpression of D-2HG dehydrogenase abolishes all mutant Idh phenotypes. UAS-Gal4 Drosophila expression system, D-2HG metabolite measurement, genetic epistasis with sod2, p53, and caspase pathway components, D-2HG dehydrogenase coexpression rescue Blood Medium 25398939
2024 ATRX loss primes IDH1 R132H glioma cells for innate immune recognition via dsRNA agonism, while IDH1 R132H expression reversibly dampens baseline innate immune gene expression and cytokine production; pharmacological or genetic inhibition of IDH1 R132H restores innate immune gene expression without interfering with ATRX-deficiency-mediated dsRNA sensitivity. Isogenic astrocytoma cell lines with combinatorial IDH1 R132H and ATRX loss (lentivirus/CRISPR), innate immune gene expression (qRT-PCR), cytokine profiling, dsRNA agonist treatment, IDH1 inhibitor rescue, in vivo xenograft T-cell infiltration Nature communications Medium 38272925
2024 Wild-type IDH1 supports PDAC cell survival after chemotherapy by sustaining mitochondrial function through α-ketoglutarate anaplerosis and maintaining antioxidant defense via NADPH generation; chemotherapy induces wild-type IDH1 expression as a resistance mechanism, and pharmacological IDH1 inhibition with ivosidenib synergizes with chemotherapy in murine PDAC models. ROS measurement after chemotherapy, TCA cycle activity assay, IDH1 induction by Western blot, siRNA knockdown of IDH1, ivosidenib pharmacological inhibition, in vivo synergy in murine PDAC models Cancer research Medium 38843355

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 IDH1 and IDH2 mutations in gliomas. The New England journal of medicine 4711 19228619
2009 Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 3113 19935646
2010 Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer cell 2260 21130701
2012 IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 1560 22343889
2011 Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 1507 22101433
2012 Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer cell 1459 23079654
2018 Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. The New England journal of medicine 1194 29860938
2013 IDH1 and IDH2 mutations in gliomas. Current neurology and neuroscience reports 462 23532369
2012 IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 443 22763442
2010 IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 427 20975057
2012 IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clinical cancer research : an official journal of the American Association for Cancer Research 358 23071358
2021 A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature 342 33762734
2017 Mutant IDH1 and seizures in patients with glioma. Neurology 210 28404805
2018 Wild-type and mutated IDH1/2 enzymes and therapy responses. Oncogene 171 29367755
2016 IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives. Journal of blood medicine 170 27621679
2017 Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence. Nature genetics 160 29180699
2011 Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. American journal of clinical pathology 146 21173122
2021 Acute myeloid leukemia with IDH1 and IDH2 mutations: 2021 treatment algorithm. Blood cancer journal 144 34083508
2016 Mutant IDH1 and thrombosis in gliomas. Acta neuropathologica 138 27664011
2015 Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198. Cancer research 124 26363012
2017 Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1. Proceedings of the National Academy of Sciences of the United States of America 123 28916733
2014 Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 122 25283382
2023 A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies. Blood cancer discovery 114 37102976
2017 Oncogenic Activities of IDH1/2 Mutations: From Epigenetics to Cellular Signaling. Trends in cell biology 112 28711227
2020 Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism. Proceedings of the National Academy of Sciences of the United States of America 107 32312817
2015 IDH1 Mutation Induces Reprogramming of Pyruvate Metabolism. Cancer research 103 26045167
2018 Mutant IDH1 Promotes Glioma Formation In Vivo. Cell reports 97 29719265
2020 SIRT2-dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases. EMBO reports 87 32141187
2017 MR Elastography Analysis of Glioma Stiffness and IDH1-Mutation Status. AJNR. American journal of neuroradiology 84 29074637
2016 Genetics and Epigenetics of Glioblastoma: Applications and Overall Incidence of IDH1 Mutation. Frontiers in oncology 80 26858939
2019 Targeting IDH1-Mutated Malignancies with NRF2 Blockade. Journal of the National Cancer Institute 77 30759236
2015 New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma. International journal of medical sciences 75 25678837
2024 Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity. Science (New York, N.Y.) 74 38991060
2019 Blockade of Glutathione Metabolism in IDH1-Mutated Glioma. Molecular cancer therapeutics 74 31548295
2019 Friend or foe-IDH1 mutations in glioma 10 years on. Carcinogenesis 72 31504231
2022 Secondary IDH1 resistance mutations and oncogenic IDH2 mutations cause acquired resistance to ivosidenib in cholangiocarcinoma. NPJ precision oncology 71 36056177
2013 Autophagy and oxidative stress in gliomas with IDH1 mutations. Acta neuropathologica 66 24150401
2022 Recent advances of IDH1 mutant inhibitor in cancer therapy. Frontiers in pharmacology 64 36091829
2013 Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 in tumors. Advances in anatomic pathology 63 23232569
2019 Novel IDH1-Targeted Glioma Therapies. CNS drugs 61 31768950
2017 Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity. Structure (London, England : 1993) 60 28132785
2023 Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability. Cancer discovery 59 36355448
2018 IDH1: Linking Metabolism and Epigenetics. Frontiers in genetics 56 30405699
2021 IDH1 mutations induce organelle defects via dysregulated phospholipids. Nature communications 53 33504762
2014 Tumor location and IDH1 mutation may predict intraoperative seizures during awake craniotomy. Journal of neurosurgery 50 25170661
2012 Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2. Current opinion in oncology 49 22080945
2014 IDH1/2 mutation detection in gliomas. Brain tumor pathology 47 25008158
2013 From genomics to the clinic: biological and translational insights of mutant IDH1/2 in glioma. Neurosurgical focus 47 23373447
2021 IDH1/IDH2 Inhibition in Acute Myeloid Leukemia. Frontiers in oncology 45 33898313
2015 LOX expression and functional analysis in astrocytomas and impact of IDH1 mutation. PloS one 45 25790191
2024 The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen. Cancer research 42 38117484
2022 ATRX loss promotes immunosuppressive mechanisms in IDH1 mutant glioma. Neuro-oncology 42 34951647
2016 Roles of IDH1/2 and TET2 mutations in myeloid disorders. International journal of hematology 42 26980223
2017 Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression. Molecular cancer research : MCR 38 28148827
2022 IDH1 Promotes Foam Cell Formation by Aggravating Macrophage Ferroptosis. Biology 37 36290297
2018 The clinical use of IDH1 and IDH2 mutations in gliomas. Expert review of molecular diagnostics 36 30427756
2012 Mutant IDH1 is required for IDH1 mutated tumor cell growth. Oncotarget 34 22885298
2019 Functional and topographic effects on DNA methylation in IDH1/2 mutant cancers. Scientific reports 33 31727977
2018 Association between IDH1/2 mutations and brain glioma grade. Oncology letters 33 30250611
2017 IDH1 and IDH2 mutations in postoperative diffuse glioma-associated epilepsy. Epilepsy & behavior : E&B 33 29172136
2015 IDH1, lipid metabolism and cancer: Shedding new light on old ideas. Biochimica et biophysica acta 33 25960387
2021 Clinical development of IDH1 inhibitors for cancer therapy. Cancer treatment reviews 32 34974243
2021 IDH1 mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis. Blood 31 33254233
2017 IDH1 Mutation Promotes Tumorigenesis by Inhibiting JNK Activation and Apoptosis Induced by Serum Starvation. Cell reports 30 28402860
2016 Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters. Oncotarget 30 27144334
2018 Immunohistochemically detected IDH1R132H mutation is rare and mostly heterogeneous in prostate cancer. World journal of urology 29 29427004
2014 Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila. Blood 28 25398939
2010 The expression and significance of IDH1 and p53 in osteosarcoma. Journal of experimental & clinical cancer research : CR 28 20459648
2017 IDH1 mutation diminishes aggressive phenotype in glioma stem cells. International journal of oncology 27 29115585
2024 Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas. Nature communications 26 38272925
2021 Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy? Cells 25 33810170
2024 Plasma ctDNA liquid biopsy of IDH1, TERTp, and EGFRvIII mutations in glioma. Neuro-oncology advances 24 38572065
2020 Sphingolipid Pathway as a Source of Vulnerability in IDH1 Glioma. Cancers 24 33050528
2017 IDH1 R132C mutation is detected in clear cell hepatocellular carcinoma by pyrosequencing. World journal of surgical oncology 23 28403884
2013 NADP+ -dependent IDH1 R132 mutation and its relevance for glioma patient survival. Medical hypotheses 23 23541771
2024 IDH1 Inhibition Potentiates Chemotherapy Efficacy in Pancreatic Cancer. Cancer research 22 38843355
2023 IDH1 mutation impairs antiviral response and potentiates oncolytic virotherapy in glioma. Nature communications 22 37880243
2021 IDH1 and IDH2 Mutations in Colorectal Cancers. American journal of clinical pathology 22 33929516
2020 Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma. Translational oncology 22 32208352
2015 Functions of idh1 and its mutation in the regulation of developmental hematopoiesis in zebrafish. Blood 22 25778530
2024 Scutellarin activates IDH1 to exert antitumor effects in hepatocellular carcinoma progression. Cell death & disease 21 38622131
2022 Tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology, and treatment. JCI insight 21 34941573
2020 mTORC2/Rac1 Pathway Predisposes Cancer Aggressiveness in IDH1-Mutated Glioma. Cancers 21 32224866
2020 IDH1 and IDH2 mutations in lung adenocarcinomas: Evidences of subclonal evolution. Cancer medicine 21 32333643
2014 Mutation and expression analysis of the IDH1, IDH2, DNMT3A, and MYD88 genes in colorectal cancer. Gene 21 24887488
2024 IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosis. Cellular & molecular biology letters 20 38172700
2022 IDH1/2 mutations in acute myeloid leukemia. Blood research 20 35197370
2021 IDH1 Non-Canonical Mutations and Survival in Patients with Glioma. Diagnostics (Basel, Switzerland) 20 33669525
2022 Ivosidenib in IDH1-mutated cholangiocarcinoma: Clinical evaluation and future directions. Pharmacology & therapeutics 19 35296436
2022 Wild-type IDH1 inhibition enhances chemotherapy response in melanoma. Journal of experimental & clinical cancer research : CR 18 36153582
2021 Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL. Journal of hematology & oncology 18 33941203
2021 Nuclear FABP7 regulates cell proliferation of wild-type IDH1 glioma through caveolae formation. Molecular oncology 18 34716958
2020 Extracellular glutamate and IDH1R132H inhibitor promote glioma growth by boosting redox potential. Journal of neuro-oncology 18 32020473
2018 RNA-Binding Protein HuR Regulates Both Mutant and Wild-Type IDH1 in IDH1-Mutated Cancer. Molecular cancer research : MCR 18 30266754
2017 IDH1 R132H mutation regulates glioma chemosensitivity through Nrf2 pathway. Oncotarget 18 28427200
2024 Clinical utility of a blood based assay for the detection of IDH1.R132H-mutant gliomas. Nature communications 17 39152110
2023 The roles of IDH1 in tumor metabolism and immunity. Future oncology (London, England) 17 36621781
2023 HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma. Scientific reports 17 37528157
2022 IDH1 Mutation Induces HIF-1α and Confers Angiogenic Properties in Chondrosarcoma JJ012 Cells. Disease markers 16 35198082
2019 IDH1 mutation promotes proliferation and migration of glioma cells via EMT induction. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 16 31983120

Missed literature

Know a paper Affinage missed for IDH1? Flag it for the maintainers and the community.

No submissions yet.