The arginine-specific reagent phenylglyoxal inactivated the active, dephosphorylated, form of Escherichia coli isocitrate dehydrogenase rapidly in a pseudo-first-order process. Both NADP+ and NADPH protected the enzyme against inactivation. Phenylglyoxal appeared to react with one arginine residue per subunit, and the extent of the reaction was proportional to the extent of the inactivation. In contrast, the phosphorylated form of isocitrate dehydrogenase did not react detectably with phenylglyoxal. The data indicate that the coenzyme-binding site of isocitrate dehydrogenase contains a reactive arginine residue that is protected by phosphorylation, and are consistent with the hypothesis that phosphorylation of the enzyme occurs close to or at its active site. ...
Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the gamma subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. This gene is a candidate gene for periventricular heterotopia. Several alternatively spliced transcript variants of this gene have been described, but only ...
True values of Michaelis constants of the NADP+-specific isocitrate dehydrogenase from Halobacterium salinarium were not very different from those of the apparent constants reported by Aitken et al. (1970). The true constants were affected by salt in a similar manner to that of the apparent constants obtained with NADP+ at fixed concentrations of 1.0-0.2mm and threo-ds-(+)-isocitrate at fixed concentrations of 2.0-0.125mm. The response of apparent Vmax. to salt concentration was highly dependent on fixed substrate concentration in solutions of sodium chloride but much less so in solutions of potassium chloride. At several levels the results emphasize the difficulty of generalizing about the salt relations of a halophil enzyme without adequate attention to substrate concentration. The enzyme has at least two different reaction mechanisms depending on salt concentration. In its physiological form (i.e. in 1.0m-potassium chloride), and also in 1.0m-sodium chloride, the reaction mechanism is ...
The level of activity of the NADP-dependent isocitrate dehydrogenase (ICDH) of E. coli ML308 is controlled by a reversible phosphorylation mechanism during growth on acetate as sole carbon source. Under such conditions the enzymes of the glyoxylate bypass, isocitrate lyase (ICL) and malate synthase are induced. This results in competition between ICDH and ICL for the available isocitrate. To allow efficient use of isocitrate via the glyoxylate bypass ICDH is phosphorylated on a single serine residue per subunit which completely inactivates it. Phosphorylation of ICDH is believed to occur at the NADP+ binding site, and so the enzyme is inactive because it cannot bind its cofactor.. ...
Isocitrate dehydrogenases (IDHs) convert isocitrate to α-ketoglutarate by oxidative decarboxylation and are thereby involved in multiple metabolic processes. Mutations in the genes encoding IDH1 and IDH2 were first reported in human gliomas in 2008 and later on also identified in a minority of patients with acute myeloid leukemia. The mutations universally affect codons 132 in IDH1 and 172 in IDH2 and result in decreased enzymatic activity. The oncogenic pathway triggered by IDH mutations may involve the activation of hypoxia-inducible factor pathway as well as the acquisition of a novel (gain of enzymatic) function consuming NADPH and generating α-hydroxyglutarate. Most intriguingly, IDH mutations are observed in ∼70-80% of grade II/III gliomas and the majority of secondary glioblastomas, but only 10% of primary glioblastomas, suggesting a different cellular origin of the gliomas, which had previously been viewed as a multistep process of malignant progression. Understanding the oncogenic ...
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Compare Isocitrate Dehydrogenase 3 (NAD ) alpha Isocitrate Dehydrogenase 3 (NAD+) alpha ELISA Kits from leading suppliers on Biocompare. View specifications, prices, citations, reviews, and more.
Synonyms for isocitric acid in Free Thesaurus. Antonyms for isocitric acid. 28 synonyms for cycle: series of events, round, circle, revolution, rotation, circle, circuit, orbit, round, tour, turn, round, rhythm, cps, cycle per second. What are synonyms for isocitric acid?
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations drive the development of gliomas and other human malignancies. Significant efforts are already underway to attempt to target mutant IDH in clinical trials. However, how mutation of IDH leads to tumorigenesis is poorly understood. Mutant IDH1 promotes epigenetic changes that promote tumorigenesis but the scale of these changes throughout the epigenome and the reversibility of these changes are unknown. Here, using both human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant IDH1-induced epigenomic reprogramming. We characterize the changes in the histone code landscape, DNA methylome, chromatin state, and transcriptional reprogramming that occur following IDH1 mutation and characterize the kinetics and reversibility of these alterations over time. We discover coordinate changes in the localization and intensity of multiple histone marks and chromatin states throughout the genome. These alterations result in
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations drive the development of gliomas and other human malignancies. Significant efforts are already underway to attempt to target mutant IDH in clinical trials. However, how mutation of IDH leads to tumorigenesis is poorly understood. Mutant IDH1 promotes epigenetic changes that promote tumorigenesis but the scale of these changes throughout the epigenome and the reversibility of these changes are unknown. Here, using both human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant IDH1-induced epigenomic reprogramming. We characterize the changes in the histone code landscape, DNA methylome, chromatin state, and transcriptional reprogramming that occur following IDH1 mutation and characterize the kinetics and reversibility of these alterations over time. We discover coordinate changes in the localization and intensity of multiple histone marks and chromatin states throughout the genome. These alterations result in
Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19. ...
TY - JOUR. T1 - Prediction of isocitrate dehydrogenase genotype in brain gliomas with MRI. T2 - Single-Shell versus Multishell Diffusion Models. AU - Figini, Matteo. AU - Riva, Marco. AU - Graham, Mark. AU - Castelli, Gian Marco. AU - Fernandes, Bethania. AU - Grimaldi, Marco. AU - Baselli, Giuseppe. AU - Pessina, Federico. AU - Bello, Lorenzo. AU - Zhang, Hui. AU - Bizzi, Alberto. PY - 2018/12/1. Y1 - 2018/12/1. N2 - Purpose: The primary aim of this prospective observational study was to assess whether diffusion MRI metrics correlate with isocitrate dehydrogenase (IDH) status in grade II and III gliomas. A secondary aim was to investigate whether multishell acquisitions with advanced models such as neurite orientation dispersion and density imaging (NODDI) and diffusion kurtosis imaging offer greater diagnostic accuracy than diffusion-tensor imaging (DTI). Materials and Methods: Diffusion MRI (b = 700 and 2000 sec/mm2) was performed preoperatively in 192 consecutive participants (113 male and ...
Cytosolic NADP-specific Isocitrate Dehydrogenase; Catalyzes Oxidation Of Isocitrate To Alpha-ketoglutarate; Levels Are Elevated During Growth On Non-fermentable Carbon Sources And Reduced During Growth On Glucose; IDP2 Has A Paralog, IDP3, That Arose From The Whole Genome Duplication
SWISS-MODEL Template Library (SMTL) entry for 1j1w. Crystal Structure Of The Monomeric Isocitrate Dehydrogenase In Complex With NADP+
The presence of genome-wide DNA hypermethylation is a hallmark of lower grade gliomas (LGG) with isocitrate dehydrogenase (IDH) mutations. Further molecular classification of IDH mutant gliomas is defined by the presence (IDHmut-codel) or absence (IDHmut-noncodel) of hemizygous codeletion of chromosome arms 1p and 19q. Despite the DNA hypermethylation seen in bulk tumors, intra-tumoral heterogeneity at the epigenetic level has not been thoroughly analyzed. To address this question, we performed the first epigenetic profiling of single cells in a cohort of 5 gliomas with IDH1 mutation using single nucleus Assay for Transposase-Accessible Chromatin with high-throughput sequencing (snATAC-seq). Using the Fluidigm HT IFC microfluidics platform, we generated chromatin accessibility maps from 336 individual nuclei, and identified variable promoter accessibility of non-coding RNAs in LGGs. Interestingly, local chromatin structures of several non-coding RNAs are significant factors that contribute to
Isocitrate dehydrogenase兔多克隆抗体(ab117539)可与人样本反应并经WB, ELISA, IHC实验严格验证。所有产品均提供质保服务,中国75%以上现货。
mitochondrion, isocitrate dehydrogenase (NADP+) activity, magnesium ion binding, 2-oxoglutarate metabolic process, isocitrate metabolic process
Abcam provides general protocols for Isocitrate Dehydrogenase Assay Kit (Colorimetric) (ab102528). Please download our pdf protocol booklet
Provides general gene info and summarizes expression data for all features of the gene IDH3B (aka ENSG00000101365, IDH3B): Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Precursor (EC 1.1.1.41)(Isocitric dehydrogenase)(NAD(+)-specific ICDH) [Source:UniProtKB/Swiss-Prot;Acc:O43837]
Frequent isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) heterozygous somatic mutations in acute myeloid leukemia (33%), glioblastoma (70% of low-grade gliomas and secondary glioblastomas), and chondrosarcomas (56%) have stimulated interest in targeting the mutant enzymes (see review by Yang and colleagues in this issue; ref 66). Mutant IDH1 and IDH2 activity changes in cell metabolic profile may be tied to cancer epigenetics (67-69). Glioblastoma genome-wide mutational analysis showed somatic IDH1 mutations occur frequently in tumors that evolved from lower-grade gliomas. Ichimura and colleagues (70) screened IDH1 gene exon 4 for mutations in 596 primary intracranial tumors. Codon 132 mutation occurred in 54% of astrocytomas, 65% of oligodendroglial tumors, and in 6% of glioblastomas (3% of primary and 50% of secondary glioblastomas). TP53 gene mutations and total 1p/19q deletions were mutually exclusive, and IDH1 mutation along with TP53 mutation or total 1p/19q loss ...
Mutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas. This mis-sense mutation results in the neomorphic reduction of isocitrate dehydrogenase resulting in an accumulation of the
Background IDH-1/2 mutations are a prognostic markers in gliomas. These mutations results in the production of 2HG. We investigated whether 2HG produced by IDH-1/2 mutant gliomas accumulates in patients plasma and urine and whether this accumulation can be used to assess IDH-1/2 mutation status.. Methods we prospectively studied PTS with intracranial gliomas and measurable disease on brain-MRI. All PTS had a partial surgical resection or a recurrent disease. The resected tissues were analyzed for IDH-1/2 mutational status; subsequently, in absence of chemotherapy and after 3 weeks from a prior surgery, a plasma and an overnight-urine samples collection were taken from consecutive PTS. 2HG concentrations were determinate by liquid chromatography tandem mass spectrometry. The statistical significance of the difference in the level of 2HG between the PTS with IDH-1/2 mutated and control group were evaluated by non parametric Mann- Whitney test.. Results we analyzed 13 PTS with IDH-1 mutated and 13 ...
Metabolic alterations driven by IDH mutation in U251 cells. In cancer cells, glycolysis upregulation generates the production of reducing equivalents NADH, whic
We previously showed that IDH1 mRNA and protein expression are elevated in tumor tissues compared with matched normal tissues (10). This suggests that IDH1 plasma level might be a useful biomarker for the diagnosis of patients with NSCLCs. We have 2 hypotheses for the elevated levels of IDH1 in blood, which are currently being investigated: IDH1 may be secreted extracellularly under exceptional circumstances or released into the blood by cell damage and cell death. In addition, plasma IDH1 levels were positively correlated with T stage in patients with NSCLCs, strongly suggesting that IDH1 might be a useful diagnostic biomarker.. In this report, we showed that the plasma IDH1 level was significantly elevated in 976 patients with NSCLCs compared with 479 healthy controls. We also tested 3 existing clinical biomarkers, CEA, CA125, and Cyfra21-1, in all the samples and compared their diagnostic efficacy to that of IDH1. Then, we established the AUCs for biomarker panels and determined the ...
Primary and metastatic brain tumors represent unique clinical challenges and often confer poor prognosis. Our research program is focused on understanding the mechanisms that drive these tumors such that vulnerabilities can be identified and therapeutically exploited. To this end, we have generated novel mouse models that not only validate the role of specific genes in tumor formation but also assess whether they are required for tumor progression and/or maintenance. High-throughput sequencing efforts have yielded an abundance of information in many cancer types. In both low grade gliomas and high grade secondary glioblastomas, a common point mutation in the metabolic gene isocitrate dehydrogenase (IDH) was identified. While these findings represented a significant breakthrough in this disease, a role for IDH in the etiology of these tumors was unclear and whether mutant IDH or products of its activity could be productively targeted for therapeutic intervention had yet to be determined. Using ...
1CW4: Active site water molecules revealed in the 2.1 A resolution structure of a site-directed mutant of isocitrate dehydrogenase.
1ISO: Determinants of cofactor specificity in isocitrate dehydrogenase: structure of an engineered NADP+ NAD+ specificity-reversal mutant.
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nbr:O3I_005215 K00031 isocitrate dehydrogenase [EC:1.1.1.42] , (GenBank) isocitrate dehydrogenase (A) MSKIKVEGTVVELDGDEMTRIIWQFIKDKLIHPYLDVNLEYYDLGIEYRDKTDDQVTIDA AEAIKRHGVGVKCATITPDEARVKEFGLKKMWRSPNGTIRNILGGTIFRAPIIISNVPRL VPGWTKPIIIGRHAFGDQYRATDFKVYQAGTVTVTFTPEDGSEPIQHEVVKMPEDGGVVM GMYNFKNSIIDFARASFNYGLQQNYPVYLSTKNTILKAYDGMFKDTFQDVFDAEFKTQFD AAGLTYEHRLIDDMVASSMKWEGGYVWACKNYDGDVQSDTVAQGFGSLGLMTSVLLTPDG KTCEAEAAHGTVTRHYRQHQQGKPTSTNPIASIFAWTRGLEHRGKLDNTPEVIGFSQTLE DVVIKTVEGGQMTKDLALLVGGDQGYLSTEEFLGALDANLARALR ...
The purpose of this assessment is to evaluate the programmatic risk of the applicant. Limited program experience, protocols and internal control governing program delivery will increase an applicants degree of risk but will not preclude the applicant from becoming a grantee. The applicants degree of risk may require additional conditions to be incorporated into the grant award pursuant to 2 CFR 200.207. Patterns or trends in programmatic risk will influence GATA training as well as the agencys monitoring plan. Appropriate support must be provided by GATU and the agency to build grantee capacity. The Process for IDHS Grants is as follows: A. IDHS provides the online questionnaire for our grantees to complete. B. Grantees complete the questionnaire for each grant they receive. C. IDHS scores the questionnaire based on the responses provided by the applicant D. The calculated responses equate to a risk profile for each of the risk categories. E. The risk profile is aligned to the applicable ...
Companion diagnostic technology to be utilized with enasidenib (AG-221/CC-90007) and AG-120 development programs for relapsed/refractory acute myeloid leukemia (AML) Approximately 20% of AML patients have an IDH mu...
Published: Jan 5, 2018 Author(s): Adam Berrington, Natalie L. Voets, Sarah J. Larkin, Nick Pennington, James Mccullagh, Richard Stacey, Christopher J. Schofield, Peter Jezzard, Stuart Clare, Tom Cadoux‐Hudson, Puneet Plaha, Olaf Ansorge, Uzay E. Emir. Journal: NMR in Biomedicine. Abnormally high levels of the oncometabolite 2‐hydroxyglutarate (2‐HG) occur in many grade II and III gliomas, and correlate with mutations in the genes of isocitrate dehydrogenase (IDH) isoforms. In vivo measurement of 2‐HG in patients, using magnetic resonance spectroscopy (MRS), has largely been carried out at 3 T, yet signal overlap continues to pose a challenge for 2‐HG detection. To combat this, several groups have proposed MRS methods.... Read More ...
(Medical Xpress) -- Three research teams have published papers in Nature, that together offer evidence suggesting that isocitrate dehydrogenase (IDH) enzyme mutations may play a role in altering activity that could have an ...
Homo sapiens isocitrate dehydrogenase 3 (NAD+) gamma (IDH3G), nuclear gene encoding mitochondrial protein, transcript variant 2, mRNA. (H00003421-R02) - Products - Abnova
Goat polyclonal Isocitrate dehydrogenase antibody validated for WB and tested in Sc. Immunogen corresponding to synthetic peptide
Four pre-designed shRNA constructs targeting isocitrate dehydrogenase 2 (NADP+), mitochondrial (IDH2), nuclear gene encoding mitochondrial protein and one scrambled control. Each shRNA construct is driven by the U6 promoter and contains a GFP reporter.
Video articles in JoVE about mutation include Isolation of Fidelity Variants of RNA Viruses and Characterization of Virus Mutation Frequency, A Standard Methodology to Examine On-site Mutagenicity As a Function of Point Mutation Repair Catalyzed by CRISPR/Cas9 and SsODN in Human Cells, Aip1p Dynamics Are Altered by the R256H Mutation in Actin, Primary Orthotopic Glioma Xenografts Recapitulate Infiltrative Growth and Isocitrate Dehydrogenase I Mutation, Combining Magnetic Sorting of Mother Cells and Fluctuation Tests to Analyze Genome Instability During Mitotic Cell Aging in Saccharomyces cerevisiae, Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules, Transgenic Rodent Assay for Quantifying Male Germ Cell Mutant Frequency, Targeted in Situ Mutagenesis of Histone Genes in Budding Yeast, Genome Editing and Directed Differentiation of hPSCs for Interrogating Lineage Determinants in Human Pancreatic Development, A Protocol for Functional Assessment of Whole-Protein
Human tissue and a mouse model of glioma demonstrate that mutant IDH1 tumors contain fewer immune cells in their microenvironment, possibly due to decreased chemotactic signals.
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S and cancers. This study inevitably suffers a number of limitations. Despite the fact that the TCGA is one of the biggest multidimensional studies, the helpful
INTRODUCTION: Malignant gliomas frequently harbor mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Studies suggest that IDH mutation contributes to tumor pathogenesis through mechanisms that are mediated by the neomorphic metabolite of the mutant IDH1 enzyme, 2-hydroxyglutarate (2-HG). The aim of this work was to synthesize and evaluate radiolabeled compounds that bind to the mutant IDH1 enzyme with the goal of enabling noninvasive imaging of mutant IDH1 expression in gliomas by positron emission tomography (PET).. METHODS: A small library of nonradioactive analogs were designed and synthesized based on the chemical structure of reported butyl-phenyl sulfonamide inhibitors of mutant IDH1. Enzyme inhibition assays were conducted using purified mutant IDH1 enzyme, IDH1-R132H, to determine the IC50 and the maximal inhibitory efficiency of the synthesized compounds. Selected compounds, 1 and 4, were labeled with radioiodine ((125)I) and/or (18)F using bromo- and phenol precursors, ...
TY - JOUR. T1 - Analysis of NADP+-dependent isocitrate dehydrogenase-1/2 gene mutations in pediatric brain tumors. T2 - Report of a secondary anaplastic astrocytoma carrying the IDH1 mutation. AU - Mascelli, Samantha. AU - Raso, Alessandro. AU - Biassoni, Roberto. AU - Severino, Mariasavina. AU - Sak, Katrin. AU - Joost, Kairit. AU - Milanaccio, Claudia. AU - Barra, Salvina. AU - Grillo-Ruggieri, Filippo. AU - Vanni, Irene. AU - Consales, Alessandro. AU - Cama, Armando. AU - Capra, Valeria. AU - Nozza, Paolo. AU - Garrè, Maria Luisa. PY - 2012/9. Y1 - 2012/9. N2 - Somatic mutations of the isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (p.R132H), have been reported for WHO grade II and III diffuse gliomas and secondary glioblastomas. We investigated IDH1/2 mutations in a retrospective series of 165 pediatric brain tumors, including atypical teratoid/rhabdoid tumors (AT/RT) and choroid plexus tumors, which had not previously ...
2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5′-diphosphate-ribose) polymerase (PARP) inhibitors. This "BRCAness" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including ...
ABSTRACT: Mitochondrial mechanisms, which may define and adjust an organism¹s thermal tolerance window to the environmental temperature regime, were studied in 2 intertidal populations of the polychaete worm Arenicola marina (L.) from the North Sea (boreal) and the White Sea (subpolar). Adaptation to lower mean annual temperatures in the subpolar White Sea population (4 vs 10°C in the North Sea) was reflected in a 2.4 times higher mitochondrial volume density in their muscle tissue. In White Sea worms acclimated to 6°C, a 10 times higher cytochrome c-oxidase (CytOx) activity was seen and the activation energy (Ea) for the oxidation of cytochrome c was reduced compared to boreal specimens acclimated to 11°C. Moreover, mitochondria from White Sea lugworms were characterised by a 2.7 times higher succinate oxidation rate and reduced Ea under mitochondrial State 3 (phosphorylating) respiration at low temperatures, as well as a higher activity of NADP-dependent isocitrate dehydrogenase (IDH) ...
Somatic gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite, (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the Tet family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation ...
Oligodendroglioma is characterized by unique clinical, pathological, and genetic features. Recurrent losses of chromosomes 1p and 19q are strongly associated with this brain cancer but knowledge of the identity and function of the genes affected by these alterations is limited. We performed exome sequencing on a discovery set of 16 oligodendrogliomas with 1p/19q co-deletion to identify new molecular features at base-pair resolution. As anticipated, there was a high rate of IDH mutations: all cases had mutations in either IDH1 (14/16) or IDH2 (2/16). In addition, we discovered somatic mutations and insertions/deletions in the CIC gene on chromosome 19q13.2 in 13/16 tumours. These discovery set mutations were validated by deep sequencing of 13 additional tumours, which revealed seven others with CIC mutations, thus bringing the overall mutation rate in oligodendrogliomas in this study to 20/29 (69%). In contrast, deep sequencing of astrocytomas and oligoastrocytomas without 1p/19q loss revealed ...
Plays a structural role to facilitate the assembly and ensure the full activity of the enzyme catalyzing the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. The heterodimer composed of the alpha (IDH3A) and beta (IDH3B) subunits and the heterodimer composed of the alpha (IDH3A) and gamma (IDH3G) subunits, have considerable basal activity but the full activity of the heterotetramer (containing two subunits of IDH3A, one of IDH3B and one of IDH3G) requires the assembly and cooperative function of both heterodimers.
May 22, 2014 Bridge to Success Targeting Mutant IDH1 in Malignant Gliomas, a collaboration between Matthew Vander Heiden of the Koch Institute, William Kaelin of the Dana-Farber Cancer Institute, and Daniel Cahill of Massachusetts General Hospital. ...
Mutations in isocitrate dehydrogenase-1 (IDH1) frequently drive acute myeloid leukemia (AML) tumorigenesis. Mutant IDH1 inhibits TET2, an enzyme involved in cytosine demethylation, resulting in disrupted DNA methylation and differentiation. However, IDH1-mutant disease is clinically distinct from TET2-mutant disease, indicating that IDH1 likely has a TET2-independent role in AML. A previous study in myeloid-specific IDH1-mutant mice revealed global changes in DNA and histone methylation and disruption of hematopoietic stem cell (HSC) differentiation, but the underlying molecular mechanisms are not fully understood. Inoue, Li, Tseng, and colleagues showed that in progenitor cells and HSCs from IDH1-mutant mice, DNA damage response (DDR) signaling was impaired by downregulation of the DNA damage sensor ATM, independent of TET2. This ATM downregulation was also observed in IDH1 mutant AML data from The Cancer Genome Atlas (TCGA). Downregulation of ATM by mutant IDH1 was associated with reduced ...