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Cooperativity between H3-K27M and PDGFRA poses multiple therapeutic vulnerabilities in human iPSC-derived diffuse midline glioma avatars (CUT&RUN)

ABSTRACT: PDGFRA and H3.3 mutations cooperate in an iPSC-based model of diffuse midline glioma to alter tumor biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225490 | GEO | 2023/06/14

REPOSITORIES: GEO

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Activity of PDGFRA inhibitor Avapritinib in H3K27M Diffuse Midline Glioma

Project description:PDGFRA is commonly altered in pediatric high grade gliomas including in histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a disease with almost no long-term survivors. We describe effective CNS penetration of a PDGFRA inhibitor with pharmacologically relevant concentrations in brain tumor tissue resulting in dramatic clinical effect and minimal side effects in a cohort of 9 pediatric high grade glioma cases.

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Cooperativity between H3.3K27M and PDGFRA poses multiple therapeutic vulnerabilities in human iPSC-derived diffuse midline glioma avatars.

Project description:Diffuse midline glioma (DMG) is a leading cause of brain tumor death in children. In addition to hallmark H3.3K27M mutations, significant subsets also harbor alterations of other genes, such as TP53 and PDGFRA. Despite the prevalence of H3.3K27M, the results of clinical trials in DMG have been mixed, possibly due to the lack of models recapitulating its genetic heterogeneity. To address this gap, we developed human iPSC-derived tumor models harboring TP53R248Q with or without heterozygous H3.3K27M and/or PDGFRAD842V overexpression. The combination of H3.3K27M and PDGFRAD842V resulted in more proliferative tumors when gene-edited neural progenitor (NP) cells were implanted into mouse brains compared to NP with either mutation alone. Transcriptomic comparison of tumors and their NP cells of origin identified conserved JAK/STAT pathway activation across genotypes as characteristic of malignant transformation. Conversely, integrated genome-wide epigenomic and transcriptomic analyses, as well as rational pharmacologic inhibition, revealed targetable vulnerabilities unique to the TP53R248Q; H3.3K27M; PDGFRAD842V tumors and related to their aggressive growth phenotype. These include AREG-mediated cell cycle control, altered metabolism, and vulnerability to combination ONC201/trametinib treatment. Taken together, these data suggest that cooperation between H3.3K27M and PDGFRA influences tumor biology, underscoring the need for better molecular stratification in DMG clinical trials.

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Cooperativity between H3-K27M and PDGFRA poses multiple therapeutic vulnerabilities in human iPSC-derived diffuse midline glioma avatars (CUT&RUN)

Project description:Cooperativity between H3-K27M and PDGFRA poses multiple therapeutic vulnerabilities in human iPSC-derived diffuse midline glioma avatars (CUT&RUN)

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Activity of PDGFRA inhibitor Avapritinib in H3K27M Diffuse Midline Glioma

Project description:Activity of PDGFRA inhibitor Avapritinib in H3K27M Diffuse Midline Glioma

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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.

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Mutations within FGFR1 and BRAF indicate superior outcome in diffuse midline gliomas, H3F3A K27M mutant

Project description:Diffuse midline glioma (DMG) is a devastating disease that is defined by its localization, by the diffuse growth of astrocytic tumor cells, and by K27M mutations within Histone H3 proteins. In a large series of such tumor samples (n=83), we show here that 12 % of these cases (n=10) harbor concomitant hotspot mutations within FGFR1 or BRAF. Respective cases were all located in midline structures and matched with reference cases of DMG using global DNA methylation profiling. TP53 mutations were significantly more frequent in BRAF/FGFR1 wild type cases. Presence of hotspot mutations within FGFR1 or BRAF was associated with a significantly better overall survival, which was independent of the patients’ age and tumor localization. Thus, our results establish the relevance of FGFR1 or BRAF mutations in DMG as a prognostic marker and open new targeted therapy options in this subgroup of DMG.

2020-12-08 | GSE161944 | GEO

H3F3A K27M Mutations Drive a Repressive Transcriptome by Modulating Chromatin Accessibility, Independent of H3K27me3 in Diffuse Midline Glioma [RNA-seq]

Project description:Heterozygous histone H3.3K27M mutation is a primary oncogenic driver of Diffuse Midline Glioma (DMG). H3.3K27M inhibits the Polycomb Repressive Complex 2 (PRC2) methyltransferase complex, leading to a global reduction and redistributing of the repressive H3 lysine 27 tri-methylation. This rewiring of the epigenome is thought to promote gliomagenesis. We established novel, isogenic DMG patient-derived cell lines that have been CRISPR-Cas9 edited to H3.3 WT or H3.3K27M alone and in combination with EZH2 and EZH1 co-deletion, inactivating PRC2 methyltransferase activity of PRC2 and eliminating H3K27me3. RNA-seq and ATAC-seq analysis of these cells revealed that K27M has a novel epigenetic effect that appears entirely independent of its effects on PRC2 function. While the loss of the PRC2 complex led to a systemic induction of gene expression (including HOX gene clusters) and upregulation of biological pathways, K27M led to a balanced gene deregulation but having an overall repressive effect on the biological pathways. Importantly, the genes uniquely deregulated by the K27M mutation, independent of methylation loss, are closely associated with changes in chromatin accessibility, with upregulated genes becoming more accessible. Notably, the PRC2-independent function of K27M appears necessary for tumorigenesis as xenografts of our H3.3K27M/EZH1/2 WT cells developed into tumors, while H3.3/EZH1/2 KO cells did not. We demonstrate that K27M mutation alters chromatin accessibility and uniquely deregulates genes, independent of K27 methylation. We further show the mutation's role in altering biological pathways and its necessity for tumor development.

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H3F3A K27M Mutations Drive a Repressive Transcriptome by Modulating Chromatin Accessibility, Independent of H3K27me3 in Diffuse Midline Glioma [ATAC-seq]

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Diffuse midline gliomas with subclonal H3F3A K27M mutation and mosaic H3.3 K27M mutant protein expression.

Project description: Not available

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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.

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