Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation Academic Article uri icon

Overview

MeSH Major

  • Brain Stem Neoplasms
  • Cell Transformation, Neoplastic
  • Embryonic Stem Cells
  • Glioma
  • Histones
  • Models, Genetic
  • Neural Stem Cells

abstract

  • Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3. The role of the H3.3K27M mutation in tumorigenesis is not fully understood. Here, we use a human embryonic stem cell system to model this tumor. We show that H3.3K27M expression synergizes with p53 loss and PDGFRA activation in neural progenitor cells derived from human embryonic stem cells, resulting in neoplastic transformation. Genome-wide analyses indicate a resetting of the transformed precursors to a developmentally more primitive stem cell state, with evidence of major modifications of histone marks at several master regulator genes. Drug screening assays identified a compound targeting the protein menin as an inhibitor of tumor cell growth in vitro and in mice.

publication date

  • December 19, 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4995593

Digital Object Identifier (DOI)

  • 10.1126/science.1253799

PubMed ID

  • 25525250

Additional Document Info

start page

  • 1529

end page

  • 33

volume

  • 346

number

  • 6216