IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by oxphos inhibition
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ABSTRACT:
PROVIDER: PRJNA1029548 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26419738_1.fastq.gz | Fastqsanger.gz | |||
| SRR26419738_2.fastq.gz | Fastqsanger.gz | |||
| SRR26419739_1.fastq.gz | Fastqsanger.gz | |||
| SRR26419739_2.fastq.gz | Fastqsanger.gz | |||
| SRR26419740_1.fastq.gz | Fastqsanger.gz |
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Project description:Rare preleukemic hematopoietic stem cells (pHSCs) harboring only the initiating mutations can be detected at the time of AML diagnosis. pHSCs are likely the origin of leukemia and a potential reservoir for relapse but remain challenging to eradicate. Using primary human samples and gene-editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show biological, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSCs). We confirm that IDH1 mutations are present in patients with clonal cytopenia of undetermined significance, but not in individuals with clonal hematopoiesis of indeterminate potential, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation with a block in differentiation, downregulation of MHC Class II genes and reprogramming of oxphos metabolism. Critically, IDH1-mutant pHSCs showed reduced metabolic activity distinct from normal HSCs and inhibition of oxphos resulted in complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wildtype HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors to prevent development and relapse of leukemia.
2023-11-30 | GSE245669 | GEO
Project description:Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequent in human glioblastomas1 and cytogenetically normal acute myeloid leukemias (AML)2. These alterations are gain-of-function mutations in that they drive the synthesis of the M-bM-^@M-^\oncometaboliteM-bM-^@M-^] R-2-hydroxyglutarate (2HG)3. It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukemogenesis. Here we report the characterization of conditional knock-in mice in which the most common IDH1 mutation, Idh1-R132H, is inserted into the endogenous murine Idh1 locus and is expressed in cells of the hematopoietic (Vav-KI) or more specifically in cells of the myeloid (LysM-KI) lineage. These mutants show increased numbers of early hematopoietic progenitors and develop splenomegaly and anemia with extramedullary hematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells exhibit both hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1/2-mutant AML. Thus, our study is the first to describe the generation of conditional Idh1-R132H-KI mice. Furthermore, our study is also the first report showing the induction of a leukemic DNA methylation signature in a modeled system and sheds light on the mechanistic links between IDH1 mutation and human AML. DNA methylation profiling in LSK cells from IDH1-R132H knock-in mice vs. control mice
2012-07-22 | E-GEOD-38687 | biostudies-arrayexpress
Project description:Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequent in human glioblastomas1 and cytogenetically normal acute myeloid leukemias (AML)2. These alterations are gain-of-function mutations in that they drive the synthesis of the “oncometabolite” R-2-hydroxyglutarate (2HG)3. It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukemogenesis. Here we report the characterization of conditional knock-in mice in which the most common IDH1 mutation, Idh1-R132H, is inserted into the endogenous murine Idh1 locus and is expressed in cells of the hematopoietic (Vav-KI) or more specifically in cells of the myeloid (LysM-KI) lineage. These mutants show increased numbers of early hematopoietic progenitors and develop splenomegaly and anemia with extramedullary hematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells exhibit both hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1/2-mutant AML. Thus, our study is the first to describe the generation of conditional Idh1-R132H-KI mice. Furthermore, our study is also the first report showing the induction of a leukemic DNA methylation signature in a modeled system and sheds light on the mechanistic links between IDH1 mutation and human AML.
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Project description:Mitochondrial dysfunction causes biophysical, metabolic and signalling changes that alter homeostasis and reprogram cells. We used a Drosophila model in which individual subunits of 4 OXPHOS complexes are knocked-down in neurons in the larval CNS. We used microarray analysis to investigate gene expression changes caused by knock down of OXPHOS subunits of complexes I, III, IV and V in neurons.
2017-03-21 | GSE96802 | GEO
Project description: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.
2024-04-28 | GSE265804 | GEO
Project description: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.
2024-04-30 | GSE266171 | GEO
Project description: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.
2024-04-30 | GSE266170 | GEO
Project description: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.
2024-04-28 | GSE264632 | GEO
Project description: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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Project description: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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