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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 [RRBS] |
| Organism |
Homo sapiens |
| 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 |
We used reduced-representation bisulfite sequencing (RRBS) of a set of human ICC cell lines to investigate DNA methylation status on the promoter region of interested genes in mIDH1 model tested (N=3 cell lines), as compared with all IDH1 WT models (N=12 cell lines)
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| Contributor(s) |
Sussman J, Wu MJ, Kammula AV, Manguso RT, Bardeesy N |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Apr 23, 2024 |
| Last update date |
Dec 10, 2024 |
| Contact name |
Robert T Manguso |
| E-mail(s) |
RMANGUSO@MGH.HARVARD.EDU, rmanguso@broadinstitute.org
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| Phone |
5084980837
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| Organization name |
Broad Institute of MIT & Harvard
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| Street address |
75 Ames Street, Rm 7053
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (15)
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| GSM8226607 |
RRBS, ICC3 in vitro |
| GSM8226608 |
RRBS, RBE in vitro |
| GSM8226609 |
RRBS, SNU1079 in vitro |
| GSM8226610 |
RRBS, ICC5 in vitro |
| GSM8226611 |
RRBS, YSCCC in vitro |
| GSM8226612 |
RRBS, ICC10 in vitro |
| GSM8226613 |
RRBS, ICC11 in vitro |
| GSM8226614 |
RRBS, ICC21 in vitro |
| GSM8226615 |
RRBS, ICC23 in vitro |
| GSM8226616 |
RRBS, ICC25 in vitro |
| GSM8226617 |
RRBS, MNNK1 in vitro |
| GSM8226618 |
RRBS, KKU100 in vitro |
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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 |
PRJNA1103856 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE264722_RAW.tar |
631.2 Mb |
(http)(custom) |
TAR (of COV) |
SRA Run Selector |
| Raw data are available in SRA |
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