H3.3 K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas

Cancer Cell. 2017 Nov 13;32(5):684-700.e9. doi: 10.1016/j.ccell.2017.09.014. Epub 2017 Oct 26.

Abstract

Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3K27M-driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3K27M-tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3K27M-pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies.

Keywords: clonal; mosaic; neurodevelopment; oncohistone; pediatric high-grade glioma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Cell Transformation, Neoplastic / genetics
  • Embryonic Stem Cells / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Glioma / genetics*
  • Glioma / metabolism
  • Glioma / pathology
  • Histones / genetics*
  • Humans
  • Mice
  • Mutation
  • Neoplasm Grading
  • Neoplasm Invasiveness
  • Neural Stem Cells / metabolism*
  • RNA Interference
  • Receptor, Platelet-Derived Growth Factor alpha / genetics*
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • X-linked Nuclear Protein / genetics
  • X-linked Nuclear Protein / metabolism

Substances

  • Histones
  • Tumor Suppressor Protein p53
  • Receptor, Platelet-Derived Growth Factor alpha
  • X-linked Nuclear Protein