Cancer Cell
Volume 35, Issue 1, 14 January 2019, Pages 140-155.e7
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Article
Histone H3.3 K27M Accelerates Spontaneous Brainstem Glioma and Drives Restricted Changes in Bivalent Gene Expression

https://doi.org/10.1016/j.ccell.2018.11.015Get rights and content
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Highlights

  • H3.3 K27M mutation enhances neural stem cell self-renewal

  • Neonatal PDGFRα activation and Trp53 loss induces supratentorial and brainstem glioma

  • H3.3 K27M preferentially accelerates hindbrain tumorigenesis

  • H3.3 K27M drives bivalent gene activation associated with neurodevelopment in DIPG

Summary

Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brainstem tumors with frequent histone H3 K27M mutations and recurrent alterations in PDGFRA and TP53. We generated genetically engineered inducible mice and showed that H3.3 K27M enhanced neural stem cell self-renewal while preserving regional identity. Neonatal induction of H3.3 K27M cooperated with activating platelet-derived growth factor receptor α (PDGFRα) mutant and Trp53 loss to accelerate development of diffuse brainstem gliomas that recapitulated human DIPG gene expression signatures and showed global changes in H3K27 posttranslational modifications, but relatively restricted gene expression changes. Genes upregulated in H3.3 K27M tumors were enriched for those associated with neural development where H3K27me3 loss released the poised state of apparently bivalent promoters, whereas downregulated genes were enriched for those encoding homeodomain transcription factors.

Keywords

histone H3 K27M
PDGFRA
DIPG
glioma
knockin
mouse
epigenetic
H3K27me3
bivalent
oncohistone

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