TY  - JOUR
AU  - Haag, Daniel
AU  - Mack, Norman
AU  - Benites Goncalves da Silva, Patricia
AU  - Statz, Britta
AU  - Clark, Jessica
AU  - Tanabe, Koji
AU  - Sharma, Tanvi
AU  - Jäger, Natalie
AU  - Jones, David T W
AU  - Kawauchi, Daisuke
AU  - Wernig, Marius
AU  - Pfister, Stefan
TI  - H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.
JO  - Cancer cell
VL  - 39
IS  - 3
SN  - 1535-6108
CY  - New York, NY
PB  - Elsevier
M1  - DKFZ-2021-00304
SP  - 407-422.e13
PY  - 2021
N1  - #EA:B062#LA:B062#2021 Mar 8;39(3):407-422.e13
AB  - 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.
KW  - DIPG (Other)
KW  - H3.3-K27M (Other)
KW  - H3K27me3 (Other)
KW  - H3K4me3 (Other)
KW  - NSC (Other)
KW  - OPC (Other)
KW  - bivalent chromatin (Other)
KW  - glioma (Other)
KW  - iPSC (Other)
KW  - orthotopic xenograft (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:33545065
DO  - DOI:10.1016/j.ccell.2021.01.005
UR  - https://inrepo02.dkfz.de/record/167358
ER  -