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

被引：75

作者：

Haag, Daniel ^{[1
,2
,3
,4
,5
]}

Mack, Norman ^{[1
,2
,3
]}

da Silva, Patricia Benites Goncalves ^{[1
,2
,3
]}

Statz, Britta ^{[1
,2
,3
]}

Clark, Jessica ^{[1
,2
,3
]}

Tanabe, Koji ^{[4
,5
]}

Sharma, Tanvi ^{[1
,2
,3
]}

Jaeger, Natalie ^{[1
,2
,3
]}

Jones, David T. W. ^{[1
,6
]}

Kawauchi, Daisuke ^{[1
,2
,3
,7
]}

Wernig, Marius ^{[4
,5
]}

Pfister, Stefan M. ^{[1
,2
,3
,8
]}

机构：

[1] Hopp Childrens Canc Ctr Heidelberg KiTZ, D-69120 Heidelberg, Germany

[2] German Canc Res Ctr, Div Pediat Neurooncol B062, D-69120 Heidelberg, Germany

[3] German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[4] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[5] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[6] German Canc Res Ctr, Pediat Glioma Res Grp, D-69120 Heidelberg, Germany

[7] Natl Ctr Neurol & Psychiat NCNP, Natl Inst Neurosci, Dept Biochem & Cellular Biol, Tokyo 1870031, Japan

[8] Heidelberg Univ Hosp, Dept Pediat Hematol & Oncol, D-69120 Heidelberg, Germany

来源：

CANCER CELL | 2021年 / 39卷 / 03期

关键词：

POTENTIAL THERAPEUTIC TARGET; PEDIATRIC HIGH-GRADE; HISTONE H3.3; PLURIPOTENT; GLIOMA; GENES; EXPRESSION; CHROMATIN; NEUROGENESIS; METHYLATION;

D O I：

10.1016/j.ccell.2021.01.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：407 / +

页数：29

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