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H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model

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...

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Main Authors: Haag, Daniel (Author) , Mack, Norman (Author) , Benites Goncalves da Silva, Patricia (Author) , Statz, Britta (Author) , Clark, Jessica (Author) , Tanabe, Koji (Author) , Sharma, Tanvi (Author) , Jäger, Natalie (Author) , Jones, David T. W. (Author) , Kawauchi, Daisuke (Author) , Wernig, Marius (Author) , Pfister, Stefan (Author)
Format: Article (Journal)
Language:English
Published: 4 February 2021
In: Cancer cell
Year: 2021, Volume: 39, Issue: 3, Pages: 407-422.e13
ISSN:1878-3686
DOI:10.1016/j.ccell.2021.01.005
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ccell.2021.01.005
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1535610821000490
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Author Notes:Daniel Haag, Norman Mack, Patricia Benites Goncalves da Silva, Britta Statz, Jessica Clark, Koji Tanabe, Tanvi Sharma, Natalie Jäger, David T.W. Jones, Daisuke Kawauchi, Marius Wernig, and Stefan M. Pfister
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Summary: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.
Item Description:Gesehen am 05.02.2021
Physical Description:Online Resource
ISSN:1878-3686
DOI:10.1016/j.ccell.2021.01.005

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