%0 Journal Article
%A Haag, Daniel
%A Mack, Norman
%A Benites Goncalves da Silva, Patricia
%A Statz, Britta
%A Clark, Jessica
%A Tanabe, Koji
%A Sharma, Tanvi
%A Jäger, Natalie
%A Jones, David T W
%A Kawauchi, Daisuke
%A Wernig, Marius
%A Pfister, Stefan
%T H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.
%J Cancer cell
%V 39
%N 3
%@ 1535-6108
%C New York, NY
%I Elsevier
%M DKFZ-2021-00304
%P 407-422.e13
%D 2021
%Z #EA:B062#LA:B062#2021 Mar 8;39(3):407-422.e13
%X 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.
%K DIPG (Other)
%K H3.3-K27M (Other)
%K H3K27me3 (Other)
%K H3K4me3 (Other)
%K NSC (Other)
%K OPC (Other)
%K bivalent chromatin (Other)
%K glioma (Other)
%K iPSC (Other)
%K orthotopic xenograft (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:33545065
%R 10.1016/j.ccell.2021.01.005
%U https://inrepo02.dkfz.de/record/167358