Format:
29
ISSN:
1878-3686
Content:
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.
Note:
Gesehen am 05.02.2021
In:
Cancer cell, Cambridge, Mass. : Cell Press, 2002, 39(2021), 3, Seite 407-422.e13, 1878-3686
In:
volume:39
In:
year:2021
In:
number:3
In:
pages:407-422.e13
In:
extent:29
Language:
English
DOI:
10.1016/j.ccell.2021.01.005
URL:
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