H3.3 K27M Mutation in Neural Progenitor Cells Drives Pediatric Glioma

Diffuse intrinsic pediatric glioma (DIPG) is a rare and aggressive brainstem tumor that frequently harbors a Lys27Met (K27M) mutation in the histone variant H3.3, which is associated with poor prognosis and correlates with TP53 mutation and platelet-derived growth factor α (PDGFRA) amplification. However, access to primary tumors is limited due to their location within the brainstem and their infiltrative nature. To experimentally model DIPG in the proper cell and developmental context, Funato and colleagues differentiated human embryonic stem (ES) cells into early neural progenitor cells (NPC) and assessed the effects of expression of H3.3 K27M together with constitutively active PDGFRα and depletion of p53 (termed P5K cells). Expression of K27M-mutant but not G34R/V-mutant H3.3 led to reduced histone H3K27 trimethylation (H3K27me3) and was sufficient to increase NPC proliferation. This proliferative effect was specific to NPCs and did not occur in ES cells, astrocytes, or lung fibroblasts. Moreover, K27M synergized with active PDGFRα expression and p53 knockdown to promote oncogenic transformation of NPCs, increase cell migration and invasion, and induce the formation of brainstem tumors in mice that resembled lower grade DIPG. Expression of K27-mutant H3.3 induced a differentiation block and resulted in gene expression patterns similar to those in primitive neuroepithelial cells, including expression of LIN28B and PLAG1. Upregulation of these genes was also detected in K27M-mutant DIPGs and was associated with genomic redistribution of repressive H3K27me3 marks in P5K cells. Finally, a chemical screen identified the menin inhibitor MI-2, which reduced the survival of K27M-transformed NPCs and primary K27M-mutant DIPG cells, restored astrocyte differentiation, and decreased the growth of established brainstem tumors in mice. Together, these studies characterize a human ES cell–based model for DIPG and identify the H3.3 K27M mutation as a driver of developmental reprogramming and oncogenesis.

Funato K, Major T, Lewis PW, Allis CD, Tabar V. Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science 2014 Nov 20 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.