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Venetoclax cooperates with ionizing radiation to attenuate Diffuse Midline Glioma tumor growth

ABSTRACT: This article highlights the radiation induced cytotoxic effect of the BCL2 inhibitor, venetoclax, in diffuse midline gliomas (DMG). 1. RNA-seq: We performed bulk RNA sequencing of DMG cells exposed to 6Gy radiation and found the genes upregulated after radiation compared to unirradiated controls. 2. DNA Repair shRNA screen: We also performed a DNA Repair shRNA screen and identified the genes which are responsible for radioresistance in DMG.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198979 | GEO | 2022/03/23

REPOSITORIES: GEO

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Venetoclax cooperates with ionizing radiation to attenuate Diffuse Midline Glioma tumor growth

Project description:Venetoclax cooperates with ionizing radiation to attenuate Diffuse Midline Glioma tumor growth

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Ataxia-telangiectasia mutated (Atm) disruption sensitizes spatially-directed H3.3K27M/TP53 diffuse midline gliomas to radiation therapy

Project description:Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by inactivating p53 mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress, presenting therapeutic opportunities. We used RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce K27M in the native H3f3a allele in a lineage- and spatially-directed manner, yielding primary mouse DMGs. Disruption of the DNA damage response kinase Ataxia-telangiectasia mutated (Atm) enhanced the efficacy of focal brain irradiation, extending mouse survival. This finding suggests that targeting ATM will enhance the efficacy of radiation therapy for p53-mutant DMG but not p53-wildtype DMG. We used spatial in situ transcriptomics and an allelic series of primary murine DMG models to identify transactivation-independent p53 activity as the key mediator of such radiosensitivity.

2023-11-04 | GSE246584 | GEO

Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation

Project description:Characterisation of a new subgroup of DMG lacking H3-K27M mutation that is defined by H3K27me3 loss and EZHIP overexpression that can be detected by IHC. These tumors are distinct from EZHIP-positive posterior fossa ependymomas and are associated with a dismal prognosis. We propose that these EZHIP/H3-WT tumors need to be considered similar to canonical DIPG/DMG, thus extending the spectrum of DMG with PRC2 inhibition beyond H3-K27M mutation

2020-03-20 | E-MTAB-8888 | biostudies-arrayexpress

Therapeutic opportunities for diffuse midline glioma identified from high-throughput combination drug screening

Project description:Diffuse midline gliomas (DMG) are a group of molecularly related malignancies occurring in midline structures of the childhood central nervous system, including thalamus, pons, and spinal cord. These cancers are characterized by high prevalence of the histone-3K27M mutation and are universally lethal, with median survival of only 9-11 months for pontine DMG (a.k.a. DIPG). In search of novel therapeutic options, we examined multiple cell models in sequential, quantitative high-throughput screens of approved and investigational drugs. This effort generated a total of 17,456 single-agent dose responses that inspired a subsequent series of HTS-enabled drug combination assessments encompassing a total of 8883 drug-drug examinations. Top combinations were validated across a panel of patient-derived cell lines representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-HDAC inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to the cellular unfolded protein response and key metabolic processes following treatment with panobinostat and marizomib. Rescue of drug induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking NAD+ production via NAMPT inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study represents the most comprehensive single-agent and combinatorial drug screen for DIPG reported to date and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores under-recognized metabolic vulnerabilities in DIPG. The combined screening outcomes represent a public resource for the DMG community.

2019-11-29 | GSE123278 | GEO

Integrated analyses reveal two molecularly and clinically distinct subtypes of H3 K27M-mutant diffuse midline gliomas with prognostic significance

Project description:We identified two subgroups of diffuse midline gliomas (DMGs) with unsupervised hierarchical cluster analyses of DNA methylation data from 149 DMGs derived from different localisations: DMG-A and DMG-B. The two epigenetic DMG-subtypes have different characteristics: DMG-A are enriched for cases with MAPK-signalling-pathway associated mutations, a methylated MGMT-promoter, medullary localisation and adult age, while DMG-B are enriched for cases with TP53-mutations, PDGFRA-amplifications, pontine localisation and paediatric patients. DMG-A have a significantly better overall survival compared to DMG-B (p < 0.001). This effect on survival is larger than that of all other parameters tested, and all other parameters are dependent on the cluster attribution. Hence, the subtype attribution based on two methylation clusters is best suited to predict survival as it integrates different molecular and clinical parameters.

2024-09-02 | GSE270993 | GEO

Unirradiated HCT116-CloneK cells

Project description:cDNA microarray study of unirradiated X-radiation (XR) sensitive HCT116-CloneK cells versus unirradiated HCT116-Clone10 cells. HCT116-Clone10 cells have similar XR response with parental HCT116 cells. Keywords = X-radiation (XR), XR sensitive, colorectal cancer cells, HCT1116 Keywords: repeat sample

2003-12-08 | GSE523 | GEO

Development of an Anti-CD99 Antibody Enables Targeting of Diffuse Midline Glioma

Project description:This article highlights the development of an antibody targeting CD99 in diffuse midline gliomas (DMG). 1. RNA-seq: We performed bulk RNA sequencing of HSJD-GBM01 cells transduced with H3.3K27M and its paired isogenic H3.3-WT cell lines to find the genes altered due to the transduction with the K27M Mutation compared to isogenic H3-WT controls. 2. RNA-seq: We also performed bulk RNA sequencing of SU-DIPG04 cells transduced with short-hair pin RNA (shRNA) targeting CD99 and with transduced with non-target controls to find the genes altered due the knockdown of CD99 compared to those transduced with non-target controls.

2025-03-28 | GSE291808 | GEO

Specific cPRC1 complexes are co-opted to mediate oncogenic gene repression in diffuse midline glioma

Project description:Summary 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 PRC2 enzymatic activity. Paradoxically, PRC2 is essential in DMG tumour cells where residual complex activity is required for oncogenic gene repression, although the molecular mechanisms acting downstream of PRC2 in this context are poorly understood. Here, we’ve discovered this oncogenic gene repression is mediated by specific canonical PRC1 (cPRC1) formations. By combining CRISPR screening, biochemical and chromatin mapping approaches with functional perturbations we show that cPRC1 complexes containing CBX4 and PCGF4 drive oncogenic gene repression downstream of H3K27me3 in DMG cells. Remarkably, the altered H3K27me3 modification landscape characteristic of these tumours rewires the distribution of cPRC1 complexes on chromatin. CBX4 and PCGF4 containing cPRC1 accumulate at sites of H3K27me3 while other cPRC1 formations are displaced. Despite accounting for <5% of cPRC1 complexes in DMG, CBX4/PCGF4-containing complexes predominate as gene repressors. Our findings link the altered distribution of H3K27me3 with imbalanced cPRC1 function, promoting oncogenic gene repression in DMG cells, revealing new disease mechanisms and highlighting potential therapeutic opportunities in this incurable childhood brain tumour.

2025-06-24 | PXD047451 | Pride

Specific cPRC1 complexes are co-opted to mediate oncogenic gene repression in diffuse midline glioma

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 PRC2 enzymatic activity. Paradoxically, PRC2 is essential in DMG tumour cells where residual complex activity is required for oncogenic gene repression, although the molecular mechanisms acting downstream of PRC2 in this context are poorly understood. Here, we’ve discovered this oncogenic gene repression is mediated by specific canonical PRC1 (cPRC1) formations. By combining CRISPR screening, biochemical and chromatin mapping approaches with functional perturbations we show that cPRC1 complexes containing CBX4 and PCGF4 drive oncogenic gene repression downstream of H3K27me3 in DMG cells. Remarkably, the altered H3K27me3 modification landscape characteristic of these tumours rewires the distribution of cPRC1 complexes on chromatin. CBX4 and PCGF4 containing cPRC1 accumulate at sites of H3K27me3 while other cPRC1 formations are displaced. Despite accounting for <5% of cPRC1 complexes in DMG, CBX4/PCGF4-containing complexes predominate as gene repressors. Our findings link the altered distribution of H3K27me3 with imbalanced cPRC1 function, promoting oncogenic gene repression in DMG cells, revealing new disease mechanisms and highlighting potential therapeutic opportunities in this incurable childhood brain tumour.

2025-06-24 | PXD058532 | Pride

Defining tumor-associated vascular heterogeneity in pediatric high-grade and diffuse midline gliomas

Project description:The blood-brain barrier (BBB) plays important roles in brain tumor pathogenesis and treatment response, yet our understanding of its function and heterogeneity within or across brain tumor types remains poorly characterized. Here we analyze the neurovascular unit (NVU) of pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG) using patient derived xenografts and natively forming glioma mouse models. We show tumor-associated vascular differences between these glioma subtypes, and parallels between PDX and mouse model systems, with DMG models maintaining a more normal vascular architecture, BBB function and endothelial transcriptional program relative to pHGG models. Unlike prior work in angiogenic brain tumors, we find that expression of secreted Wnt antagonists do not alter the tumor-associated vascular phenotype in DMG tumor models. Together, these findings highlight vascular heterogeneity between pHGG and DMG and differences in their response to alterations in developmental BBB signals that may participate in driving these pathological differences.

2021-09-01 | GSE179372 | GEO

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