H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model

Cancer Cell. 2021 Mar 8;39(3):407-422.e13. doi: 10.1016/j.ccell.2021.01.005. Epub 2021 Feb 4.


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 histone H3 mutation leading to a lysine 27-to-methionine exchange (H3K27M). We engineered human induced pluripotent stem cells (iPSCs) to carry an inducible H3.3-K27M allele in the endogenous locus and studied the effects of the mutation in different disease-relevant neural cell types. H3.3-K27M upregulated bivalent promoter-associated developmental genes, producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in neural stem cells (NSCs) and to a lesser extent in oligodendrocyte progenitor cells (OPCs). Only NSCs gave rise to tumors upon induction of H3.3-K27M and TP53 inactivation in an orthotopic xenograft model recapitulating human DIPGs. In NSCs, H3.3-K27M leads to maintained expression of stemness and proliferative genes and a premature activation of OPC programs that together may cause tumor initiation.

Keywords: DIPG; H3.3-K27M; H3K27me3; H3K4me3; NSC; OPC; bivalent chromatin; glioma; iPSC; orthotopic xenograft.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Stem Neoplasms / genetics*
  • Brain Stem Neoplasms / parasitology*
  • Cell Line
  • Female
  • Glioma / genetics*
  • Glioma / pathology*
  • HEK293 Cells
  • Histones / genetics*
  • Humans
  • Induced Pluripotent Stem Cells / pathology*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neural Stem Cells / pathology*


  • Histones