Project description:Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstem with currently no curative treatment available. The vast majority of DIPGs carry a mutation in histone H3 leading to a lysine 27-to-methionine exchange (H3K27M). The H3K27M mutation has been shown to inhibit EZH2, the catalytic subunit of the polycomb repressive complex 2, which presumably leads to global reduction of H3K27 trimethylation and upregulation of tumor-driving genes. However, the exact pathomechanism and cellular context remain elusive. Recent single cell transcriptome data suggested the DIPG cell of origin to be of oligodendroglial lineage, whereas in vivo studies demonstrated neural stem or progenitor cells (NPCs, NSCs) to be susceptible for malignant transformation upon H3K27M expression. Here, we used targeted human induced pluripotent stem cells (iPSCs) carrying an inducible H3.3-K27M allele in the endogenous H3F3A locus together with specific differentiation methods to study the effects of the mutation in disease-relevant cell identities of the neural lineage. Phenotypic, transcriptomic, and chromatin immunoprecipitation sequencing (ChIP-seq) analyses revealed a distinct role of H3.3-K27M for deregulating bivalent promoter-associated developmental genes producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in NSCs and to a lesser extent in oligodendroglial progenitor cells (OPCs) but not in astroglial-restricted precursors. Importantly, we demonstrated that only NSCs but not OPCs gave rise to tumors upon induction of the H3.3-K27M and TP53 inactivation in an orthotopic xenograft model faithfully recapitulating human DIPGs. Thus, we provide evidence that indeed only NSCs can develop H3.3-K27M-driven DIPG-like tumors but that the mutation actively drives acquisition of oligodendroglial characteristics, thus explaining the different observations of cell identity. Identification of the originating cell type may help to determine specific vulnerabilities of this tumor for developing targeted therapies.

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Expression of histone 3 wildtype vs. histone 3 (K27M) using MiniCoopR in zebrafish

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