Journal Article

DKFZ-2021-00304

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.

Haag, D. (First author)DKFZ* ; Mack, N.DKFZ* ; Benites Goncalves da Silva, P.DKFZ* ; Statz, B.DKFZ* ; Clark, J.DKFZ* ; Tanabe, K. ; Sharma, T.DKFZ* ; Jäger, N.DKFZ* ; Jones, D. T. W.DKFZ* ; Kawauchi, D.DKFZ* ; Wernig, M. ; Pfister, S. (Last author)DKFZ*

2021
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.ccell.2021.01.005

Abstract: 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.

Keyword(s): DIPG ; H3.3-K27M ; H3K27me3 ; H3K4me3 ; NSC ; OPC ; bivalent chromatin ; glioma ; iPSC ; orthotopic xenograft

Note: #EA:B062#LA:B062#2021 Mar 8;39(3):407-422.e13

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)
3. Pediatric Glioma (B360)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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