H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model
| Autor: | Patricia Benites Goncalves da Silva, Daisuke Kawauchi, Britta Statz, Koji Tanabe, Norman Mack, Stefan M. Pfister, David T.W. Jones, Daniel Haag, Jessica Clark, Marius Wernig, Tanvi Sharma, Natalie Jäger |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Cancer Research Cell type Induced Pluripotent Stem Cells Mice SCID Tumor initiation Biology Cell Line Histones Mice 03 medical and health sciences 0302 clinical medicine Neural Stem Cells Mice Inbred NOD Glioma medicine Animals Brain Stem Neoplasms Humans Induced pluripotent stem cell Neural cell medicine.disease Neural stem cell HEK293 Cells 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research H3K4me3 Female Bivalent chromatin |
| Zdroj: | Cancer Cell. 39:407-422.e13 |
| ISSN: | 1535-6108 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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