Abstract IA31: Stalled developmental programs at the root of K27M mutant gliomas and other pediatric brain tumors

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Abstract Childhood brain tumors have suspected prenatal origins. We showed that H3K27M in gliomas impairs the production and the spread of the repressive H3K27me3 mark from PRC2 high-affinity sites. Neither the recruitment of PRC2 to its nucleation sites nor the deposition of the H3K27me3 mark in the proximity of those sites was affected by the mutation. However, our findings indicate that as the marks cannot spread to establish the proper silencing landscape, further lineage specification, a major role of PRC2, is not possible, and the cell is stalled in an early epigenetic and progenitor state, indefinitely multiplying without being able to further differentiate. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >44,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 119 distinct cell populations and defined regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage, embryonal tumors with multilayered rosettes fully recapitulate a cortical neuronal lineage, atypical teratoid-rhabdoid tumors originate outside of the neuro-ectoderm, while diffuse intrinsic pontine gliomas resemble a pontine astrocytic progenitor and differentiate upon removal of driver mutation H3K27M. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies mirroring transcriptional programs of the corresponding normal lineages. We identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions. Citation Format: Nada Jabado. Stalled developmental programs at the root of K27M mutant gliomas and other pediatric brain tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA31.