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

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: GSE225491 | GEO | 2026/03/01

REPOSITORIES: GEO

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

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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 (RNA-Seq)

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

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

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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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