Mutant IDH modulates suppressive myeloid populations in malignant glioma
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE268118 | GEO | 2024/05/29
REPOSITORIES: GEO
Similar Datasets
Project description:This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled brain metastasis. The study will have three phases, Phase 1, Phase 2a and Phase 2b.
| 92735 | ecrin-mdr-crc
Project description:To understand the diversity of expression states within IDH-mutant astrocytoma tumors, we profiled 6341 cells from 10 tumors by single cell RNA-seq
2017-03-31 | GSE89567 | GEO
Project description:Mutant IDH modulates suppressive myeloid populations in malignant glioma
| PRJNA1114709 | ENA
Project description:Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas (ODG), and IDH-wildtype glioblastomas (GBM). GBM display genome instability, which may result from two genetic events leading to massive chromosome alterations: chromothripsis (CT) and whole-genome duplication (WGD). The better prognosis of the latter may be related to their genome stability compared to GBM. Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening.
2024-12-24 | E-MTAB-13542 | biostudies-arrayexpress
Project description:Recent single-cell transcriptomic studies report that IDH-mutant gliomas share a common hierarchy of cellular phenotypes, independent of genetic subtype. However, the genetic differences between IDH-mutant glioma subtypes are prognostic, predictive of response to chemotherapy, and correlate with distinct tumor microenvironments. To reconcile these findings, we profiled 22 human IDH-mutant gliomas via single-cell assay for transposase-accessible chromatin (scATAC-seq). We determined the cell-type specific differences in transcription-factor expression and associated regulatory grammars between IDH-mutant glioma subtypes. We find that while IDH-mutant gliomas do share a common distribution of cell types, there are significant differences in the expression and targeting of transcription factors that regulate glial identity and cytokine elaboration. We knocked out the chromatin-remodeler ATRX, which suffers loss-of-function alterations in most IDH-mutant astrocytomas, in an IDH-mutant immunocompetent intracranial murine model. We find that both human ATRX-mutant gliomas and murine ATRX-knockout gliomas are more heavily infiltrated by immunosuppressive monocytic-lineage cells derived from circulation than ATRX-intact gliomas, in an IDH-mutant background. ATRX knockout in murine glioma recapitulates gene expression and open-chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. ATRX knockout in murine glioma recapitulates gene expression and open chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. Through single-cell cleavage under targets and tagmentation assays and meta-analysis of public data, we show that ATRX loss leads to a global depletion in CCCTC-binding factor association with DNA, gene dysregulation along associated chromatin loops, and protection from therapy-induced senescence.
2021-10-20 | GSE155430 | GEO
Project description:Single cell data from IDH mutant astroxytoma and IDH wildtype GBM tumor specimen
| PRJNA961045 | ENA
Project description:p53 prevents tumor initiation and progression by adapting cell fate via transcriptional regulation of target gene networks. Here, we find that cancer associated mutations in isocitrate dehydrogenase (IDH) can uncouple p53 activity from tumor suppression by perturbing chromatin states that determine target gene expression. Mutant IDH impairs tumor regressions and promotes outgrowth of cancer cells with transcriptionally active, wild type p53 in a mouse model of liver cancer where restoration of p53 activity results in tumor clearance. Mutant IDH alters p53 target gene expression through the oncometabolite 2-hydroxyglutarate (2-HG), an inhibitor of alpha-ketoglutarate (KG) dependent chromatin remodeling enzymes, without preventing p53 accumulation or global genomic binding. Rather, mutant IDH alters chromatin accessibility landscapes that dictate target gene expression. Mutant IDH interferes with the expression of pro-apoptotic p53 targets, including the death ligand receptor Fas that enables p53 dependent liver tumor regressions. Pharmacological inhibition of mutant IDH in TP53 wildtype cholangiocarcinoma cells, a tumor type where p53 and IDH mutations are mutually exclusive, potentiates p53 target gene expression and sensitizes cells to Fas ligand and chemotherapy induced apoptosis. Therefore, we implicate disruption of p53 target gene regulation as a reversable, oncogenic feature of cancer associated IDH mutations.
2025-04-30 | GSE279555 | GEO
Project description:p53 prevents tumor initiation and progression by adapting cell fate via transcriptional regulation of target gene networks. Here, we find that cancer associated mutations in isocitrate dehydrogenase (IDH) can uncouple p53 activity from tumor suppression by perturbing chromatin states that determine target gene expression. Mutant IDH impairs tumor regressions and promotes outgrowth of cancer cells with transcriptionally active, wild type p53 in a mouse model of liver cancer where restoration of p53 activity results in tumor clearance. Mutant IDH alters p53 target gene expression through the oncometabolite 2-hydroxyglutarate (2-HG), an inhibitor of alpha-ketoglutarate (KG) dependent chromatin remodeling enzymes, without preventing p53 accumulation or global genomic binding. Rather, mutant IDH alters chromatin accessibility landscapes that dictate target gene expression. Mutant IDH interferes with the expression of pro-apoptotic p53 targets, including the death ligand receptor Fas that enables p53 dependent liver tumor regressions. Pharmacological inhibition of mutant IDH in TP53 wildtype cholangiocarcinoma cells, a tumor type where p53 and IDH mutations are mutually exclusive, potentiates p53 target gene expression and sensitizes cells to Fas ligand and chemotherapy induced apoptosis. Therefore, we implicate disruption of p53 target gene regulation as a reversable, oncogenic feature of cancer associated IDH mutations.
2025-04-30 | GSE279597 | GEO
Project description:Gain-of-function IDH mutations define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylase enzymes, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes are critical for the dynamic regulation of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH1 mutant gliomas exhibit hyper-methylation at CTCF binding sites, leading to reduced binding of this methylation-sensitive insulator protein. Loss of CTCF binding is associated with a loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and reduces PDGFRA expression. Conversely, CRISPR-mediated disruption of the CTCF binding sequence in IDH wildtype gliomaspheres induces PDGFRA expression and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression. CTCF occupancy characterization and histone H3K27 acetylation profiling in IDH1 mutant and wild-type glioma patient specimens and culture models. ChIP-seq raw data is to be made available through dbGaP (controlled access) due to patient privacy concerns.
2015-12-23 | E-GEOD-70991 | biostudies-arrayexpress
Project description:Mutations in Isocitrate dehydrogenase 1/2 (IDH) are early initiating events in Acute Myeloid Leukemia (AML) associated with high-risk disease. The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Utilizing integrated single cell genotyping and gene expression, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify transcriptomic programs associated with subclones harboring mutations in NPM1, NRAS, and SRSF2. Furthermore, these clones had diverse responses to treatment with combination IDH inhibitors and chemotherapy including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. In patients that relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated MHC Class II antigen presentation at relapse. Applying this framework to IDH2-mutant clonal hematopoiesis reveals an upregulation of IDH2-associated pathways, including inflammation, early at the pre-leukemic stage. In conclusion, we provide a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and under therapy, with implications for precision medicine.
2025-05-21 | GSE230559 | GEO