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Series GSE265854 Query DataSets for GSE265854
Status Public on Apr 28, 2024
Title Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity [human WGBS]
Organism Homo sapiens
Experiment type Methylation profiling by high throughput sequencing
Summary Isocitrate Dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores anti-tumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show striking, selective hypermethylation and silencing of the cytoplasmic dsDNA sensor, CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase activates cGAS, triggering viral mimicry and stimulating anti-tumor immunity. Thus, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous reverse transcriptase activity to the mechanism of action of an FDA-approved oncology drug.
 
Overall design This study used the mIDH inhibitor, AG120 (Servier Pharmaceuticals). Human ICC (SNU1079) cells were treated for five days with either DMSO or 1 μM mIDH inhibitor (AG120). Where indicated, 10ng/mL IFNγ was added for the final two days of culturing. Cells were collected for WGBS on the fifth day.
 
Contributor(s) Wu M, Kammula AV, Manguso RT, Bardeesy N
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Submission date Apr 25, 2024
Last update date Apr 30, 2024
Contact name Robert Manguso
E-mail(s) rmanguso@broadinstitute.org
Organization name Broad Institute of MIT and Harvard
Street address 75 Ames Street
City Cambridge
State/province MA
ZIP/Postal code 02142
Country USA
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (12)
GSM8230087 WGBS, SNU1079 in vitro, DMSO, Replicate 1
GSM8230088 WGBS, SNU1079 in vitro, DMSO, Replicate 2
GSM8230089 WGBS, SNU1079 in vitro, DMSO, Replicate 3
This SubSeries is part of SuperSeries:
GSE264730 Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity
Relations
BioProject PRJNA1104550

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE265854_RAW.tar 3.6 Gb (http)(custom) TAR (of COV)
SRA Run SelectorHelp
Raw data are available in SRA

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