2HG concentration in human IDH1m cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Human Homo Sapiens
TISSUE(S): Glioma Cells
DISEASE(S): Cancer
SUBMITTER: 
Maureen Kachman
PROVIDER: ST000824 | MetabolomicsWorkbench | Fri Jul 14 00:00:00 BST 2017
REPOSITORIES: MetabolomicsWorkbench
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Project description:The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1) which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen dose-dependently blocked the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9M3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant - but not IDH1-wildtype – glioma cells without appreciable changes in genome wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects. Samples were maintained in either DMSO or 1.5uM 5198 for 2 passages up to 20 passages. Biological replicates for each passage and treatment was collected and genomic DNA was extracted and analyzed on the Illumina 450K Methylation platform for a total of 16 samples.
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Project description:Mouse neural stem cells were generated from conditional knock-in mice. Mutant IDH1 is conditionally expressed following expression of Cre-recombinase. Cre-recombinase was incorporated in vitro via adenoviral-Cre recombinase. Addtionally, adenoviral-GFP was also used to control for effects of adenoviral infection. D-2HG, the metabolic product of IDH1-R132H, was detected in cell lines post-cre transduction
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Project description:Human acute myeloid leukemia HL60 cells were transduced with IDH1-WT or IDH1-R132H, and corresponding sub-clones were generated by FACS. In a first series of experiments, cells expressing wt and mutant IDH1were treated with either 1µM all-trans retinoic acid (ATRA) or with vehicle (DMSO) for 24 hrs, resulting in 4 groups of samples (WT-CTRL, WT-ATRA, Mutant-CTRL, Mutant-ATRA). In a second series of assays, WT-IDH1 cells were pre-treated for 2 days with either 100 µM octyl ester of (R)-2-hydroxyglutarate ((R)-2-HG) or 1-octanol (octyl), and then treated with 1 µM ATRA or vehicle for 24 hrs, again resulting in 4 groups of samples (Octyl-CTRL, Octyl-ATRA, 2HG-CTRL, 2HG-ATRA). All assays were performed in triplicate (4 replicates for Mutant-CTRL and Mutant-ATRA).
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