Methylation profile of H3K27M-mutant diffuse gliomas with a non-midline location 2
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1092689 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Genome wide DNA methylation profiling of an H3K27M-mutant diffuse gliomas with a non-midline location. The Illumina Infinium Human EPICV2 DNA methylation Beadchip was used to obtain DNA methylation profiles across more than 935,000 CpGs from a FFPE sample.
2025-05-01 | GSE262640 | GEO
Project description:Genome wide DNA methylation profiling of an H3K27M-mutant diffuse gliomas with a non-midline location. The Illumina Infinium Human EPIC DNA methylation Beadchip was used to obtain DNA methylation profiles from more than 850,000 CpGs from a FFPE sample.
2025-05-01 | GSE262639 | GEO
Project description:Methylation profile of H3K27M-mutant diffuse gliomas with a non-midline location 1
| PRJNA1092682 | ENA
Project description:GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas
| PRJNA776146 | ENA
Project description:Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal central nervous system (CNS) tumors that occur most commonly in children and young adults1. Average life expectancy is ten months from diagnosis, and 5-year survival is less than 1%2. Palliative radiotherapy is the only established treatment3, and neither cytotoxic nor targeted pharmacological approaches have demonstrated anti-tumor responses or improved prognosis to date3,4. We previously discovered that the disialoganglioside GD2 is highly and uniformly expressed on H3K27M+ DMG cells and demonstrated that intravenously (IV) administered GD2.4-1BB.z chimeric antigen receptor (CAR) T-cells eradicated established DMGs in patient-derived orthotopic murine models5, thereby providing the rationale for a first-in-human/first-in-child Phase 1 clinical trial (NCT04196413). Because CAR T-cell-induced inflammation and edema of the brainstem can result in obstructive hydrocephalus, increased intracranial pressure, and dangerous tissue shifts, a number of neurocritical care precautions were incorporated in the clinical trial design and management plan. Here we present the clinical experience from the first four patients with H3K27M+ DMG treated with GD2-CAR T-cells at dose level 1 (DL1; 1e6 GD2-CAR T-cells/kg administered IV). Patients who exhibited clinical benefit were eligible for subsequent administrations of GD2-CAR T-cells. Given preclinical evidence for increased CAR T-cell potency6, and the potential for diminished immunogenicity with locoregional administration, second doses were administered intracerebroventricularly (ICV) through an Ommaya catheter to three patients. As predicted from preclinical models, toxicity was largely related to the neuroanatomical location of the tumors and was reversible with intensive supportive care. Although GD2 is expressed at low levels in normal neural tissue, no evidence of on-target, off-tumor toxicity was observed. Three of four patients exhibited clinical and radiographic improvement, underscoring the promise of this approach for H3K27M+ DMG therapy. Correlative studies of serum and CSF revealed marked proinflammatory cytokine production following GD2 CAR T cell administration and single cell transcriptomic analysis of 65,598 single cells from CAR T cell products and patient CSF has begun to reveal differences that correlate with the heterogeneity between subjects and routes of administration.
2022-02-07 | GSE186802 | GEO
Project description:Anaplastic ependymoma and H3K27M-mutant diffuse midline glioma were analyzed and compared by scRNA-seq.
2024-02-28 | GSE245674 | GEO
Project description:Pediatric diffuse midline gliomas harboring the Histone 3 lysine 27-to-methionine mutation (H3K27M-pDMG) represent a highly heterogenous group of brain tumors characterized by intrinsic resistance to radiation therapy, the current standard of care. Recent evidence suggests that intratumor small extracellular vesicle (sEV)-mediated signaling plays an oncogenic role among glioma stem cell populations. However, the dynamics and functional roles of H3K27M-pDMG derived sEVs in the context of radiation-induced stress remain unclear. In this study, we characterize sEV uptake dynamics between H3K27M tumor cells, identify potential sEV surface proteins involved in the process, and demonstrate that radioresistant (RR) H3K27M-pDMG-derived sEVs confer radioprotective effects to radiosensitive (RS) H3K27M-pDMG cells at the population level. RR-sEVs induce metabolic and gene expression changes in RS cell populations within the timescale of EV uptake and internalization, leading to improved DNA repair following radiation-induced stress. Furthermore, we identified the proteins, microRNAs (miRNAs), and metabolites present in RR-sEVs, shedding light on the molecular cargo that may be responsible for these effects. Our findings provide insights into the intrinsic radioresistant properties mediated by H3K27M-pDMG-derived sEVs and propose novel targets for disrupting radioresistant intratumoral communication in H3K27M-pDMGs.
2025-06-02 | GSE286943 | GEO
Project description:Pediatric diffuse midline gliomas harboring the Histone 3 lysine 27-to-methionine mutation (H3K27M-pDMG) represent a highly heterogenous group of brain tumors characterized by intrinsic resistance to radiation therapy, the current standard of care. Recent evidence suggests that intratumor small extracellular vesicle (sEV)-mediated signaling plays an oncogenic role among glioma stem cell populations. However, the dynamics and functional roles of H3K27M-pDMG derived sEVs in the context of radiation-induced stress remain unclear. In this study, we characterize sEV uptake dynamics between H3K27M tumor cells, identify potential sEV surface proteins involved in the process, and demonstrate that radioresistant (RR) H3K27M-pDMG-derived sEVs confer radioprotective effects to radiosensitive (RS) H3K27M-pDMG cells at the population level. RR-sEVs induce metabolic and gene expression changes in RS cell populations within the timescale of EV uptake and internalization, leading to improved DNA repair following radiation-induced stress. Furthermore, we identified the proteins, microRNAs (miRNAs), and metabolites present in RR-sEVs, shedding light on the molecular cargo that may be responsible for these effects. Our findings provide insights into the intrinsic radioresistant properties mediated by H3K27M-pDMG-derived sEVs and propose novel targets for disrupting radioresistant intratumoral communication in H3K27M-pDMGs.
2025-06-02 | GSE286941 | GEO
Project description:Pediatric diffuse midline gliomas harboring the Histone 3 lysine 27-to-methionine mutation (H3K27M-pDMG) represent a highly heterogenous group of brain tumors characterized by intrinsic resistance to radiation therapy, the current standard of care. Recent evidence suggests that intratumor small extracellular vesicle (sEV)-mediated signaling plays an oncogenic role among glioma stem cell populations. However, the dynamics and functional roles of H3K27M-pDMG derived sEVs in the context of radiation-induced stress remain unclear. In this study, we characterize sEV uptake dynamics between H3K27M tumor cells, identify potential sEV surface proteins involved in the process, and demonstrate that radioresistant (RR) H3K27M-pDMG-derived sEVs confer radioprotective effects to radiosensitive (RS) H3K27M-pDMG cells at the population level. RR-sEVs induce metabolic and gene expression changes in RS cell populations within the timescale of EV uptake and internalization, leading to improved DNA repair following radiation-induced stress. Furthermore, we identified the proteins, microRNAs (miRNAs), and metabolites present in RR-sEVs, shedding light on the molecular cargo that may be responsible for these effects. Our findings provide insights into the intrinsic radioresistant properties mediated by H3K27M-pDMG-derived sEVs and propose novel targets for disrupting radioresistant intratumoral communication in H3K27M-pDMGs.
2025-06-02 | GSE286945 | GEO
Project description:Diffuse midline glioma (DMG) is a fatal childhood brain tumour characterised primarily by mutant histone H3 (H3K27M). H3K27M causes a global reduction in Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 by inhibiting the enzymatic activity of the complex. Paradoxically, PRC2 histone methyltransferase activity is essential in for oncogenic gene repression in DMG tumour cells though downstream molecular mechanisms that are poorly understood. Here, we discover that this oncogenic gene repression is mediated by specific canonical PRC1 (cPRC1) formations containing CBX4. By combining CRISPR screening, biochemical and chromatin mapping approaches with functional perturbations we show that cPRC1 complexes containing CBX4-cPRC1 is co-opted to drive repression downstream of H3K27me3 in DMG cells. Remarkably, the altered H3K27me3 landscape characteristic of H3K27M-mutant DMG rewires the distribution of distinct cPRC1 complexes such that CBX4-cPRC1 accumulates at sites of H3K27me3 while other cPRC1 formations are reduced. Despite CBX4-cPRC1 accounting for less than 5% all cPRC1 H3K27M-mutant DMG, it acts as the predominant repressor of (Polycomb target) neural differentiation genes in this setting. Our findings link the altered distribution of H3K27me3 with imbalances of CBX-cPRC1 functions and consequent oncogenic gene repression, revealing new disease mechanisms and potential therapeutic opportunities in this incurable childhood brain tumour.
2025-06-24 | PXD047401 | Pride