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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Apr 28, 2024 |
| Title |
Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity [mouse WGBS] |
| Organism |
Mus musculus |
| Experiment type |
Methylation profiling by high throughput sequencing
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| 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.
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| Overall design |
This study used the mIDH inhibitor, AG120 (Servier Pharmaceuticals). Murine ICC (2205) 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. The normal livers were from vehicle- or AG120-treated mice for 6 days.
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| Contributor(s) |
Wu MJ, Kammula AV, Manguso RT, Bardeesy N |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Apr 24, 2024 |
| Last update date |
Apr 30, 2024 |
| Contact name |
Robert Manguso |
| E-mail(s) |
rmanguso@broadinstitute.org
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| Organization name |
Broad Institute of MIT and Harvard
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| Street address |
75 Ames Street
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (16)
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| GSM8229479 |
WGBS, 2205 in vitro, IFNg, Replicate 1 |
| GSM8229480 |
WGBS, 2205 in vitro, IFNg, Replicate 2 |
| GSM8229481 |
WGBS, 2205 in vitro, IFNg, Replicate 3 |
| GSM8229482 |
WGBS, 2205 in vitro, AG120, Replicate 1 |
| GSM8229483 |
WGBS, 2205 in vitro, AG120, Replicate 2 |
| GSM8229484 |
WGBS, 2205 in vitro, AG120, Replicate 3 |
| GSM8229485 |
WGBS, 2205 in vitro, AG120+IFNg, Replicate 1 |
| GSM8229486 |
WGBS, 2205 in vitro, AG120+IFNg, Replicate 2 |
| GSM8229487 |
WGBS, 2205 in vitro, AG120+IFNg, Replicate 3 |
| GSM8229488 |
WGBS, normal liver, Vehicle, Replicate 1 |
| GSM8229489 |
WGBS, normal liver, Vehicle, Replicate 2 |
| GSM8229490 |
WGBS, normal liver, AG120, Replicate 1 |
| GSM8229491 |
WGBS, normal liver, AG120, Replicate 2 |
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| This SubSeries is part of SuperSeries: |
| GSE264730 |
Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity |
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| Relations |
| BioProject |
PRJNA1104239 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE265806_RAW.tar |
3.6 Gb |
(http)(custom) |
TAR (of COV) |
SRA Run Selector |
| Raw data are available in SRA |
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