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000167358 1001_ $$0P:(DE-He78)4e91a6c1d8301c9e964b25e084804264$$aHaag, Daniel$$b0$$eFirst author$$udkfz
000167358 245__ $$aH3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.
000167358 260__ $$aNew York, NY$$bElsevier$$c2021
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000167358 520__ $$aDiffuse 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.
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000167358 650_7 $$2Other$$aDIPG
000167358 650_7 $$2Other$$aH3.3-K27M
000167358 650_7 $$2Other$$aH3K27me3
000167358 650_7 $$2Other$$aH3K4me3
000167358 650_7 $$2Other$$aNSC
000167358 650_7 $$2Other$$aOPC
000167358 650_7 $$2Other$$abivalent chromatin
000167358 650_7 $$2Other$$aglioma
000167358 650_7 $$2Other$$aiPSC
000167358 650_7 $$2Other$$aorthotopic xenograft
000167358 7001_ $$0P:(DE-He78)e73a0a4fab40344d89d693cbe1df3109$$aMack, Norman$$b1$$udkfz
000167358 7001_ $$0P:(DE-He78)3c0df100616117ded2bf0f9cc3133de7$$aBenites Goncalves da Silva, Patricia$$b2$$udkfz
000167358 7001_ $$0P:(DE-He78)5f5223d7faa01a1e1df8a30d85cff5b0$$aStatz, Britta$$b3$$udkfz
000167358 7001_ $$0P:(DE-HGF)0$$aClark, Jessica$$b4
000167358 7001_ $$aTanabe, Koji$$b5
000167358 7001_ $$0P:(DE-He78)36e1ec4777d5b7887344177dca41eae9$$aSharma, Tanvi$$b6$$udkfz
000167358 7001_ $$0P:(DE-He78)bff9e3e3d86865d2b0836bb8f3ce98f3$$aJäger, Natalie$$b7$$udkfz
000167358 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David T W$$b8$$udkfz
000167358 7001_ $$0P:(DE-He78)0ac2bd1a9fb1823a351ee4434d80808b$$aKawauchi, Daisuke$$b9$$udkfz
000167358 7001_ $$aWernig, Marius$$b10
000167358 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b11$$eLast author$$udkfz
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