Journal
CANCER CELL
Volume 39, Issue 3, Pages 407-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2021.01.005
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Funding
- Bear Necessities Foundation
- Stanford Child Health Research Institute Morgridge Faculty Scholar Award
- Emerson Collective
- National Brain Tumor Society (United States)
- Rally Foundation
- Childhood Brain Tumor Foundation
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The study found that the H3.3-K27M mutation has different effects on different neural cell types, with only neural stem cells capable of giving rise to tumors in an in vivo model by inducing H3.3-K27M and TP53 inactivation.
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.
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