德国海德堡大学
据研究人员介绍,弥漫性桥脑神经胶质瘤(DIPG)是一种侵袭性的儿童脑干肿瘤,目前尚无治疗方法。绝大多数DIPG携带组蛋白H3突变,导致第27位赖氨酸与甲硫氨酸的交换(H3K27M)。
研究人员设计了人类诱导型多能干细胞(iPSC),可在内源性位点携带可诱导的H3.3-K27M等位基因,并研究了该突变在与疾病相关的不同神经细胞类型中的作用。H3.3-K27M上调了与二价启动子相关的发育基因,并在不同细胞类型中产生了不同的结果。H3.3-K27M对iPSC是致死性的,但它增加了神经干细胞(NSC)中的增殖,而对少突胶质细胞祖细胞(OPC)的增殖贡献较小。
在重现人类DIPG的原位异种移植模型中,只有HSC诱导H3.3-K27M和TP53失活才能引起肿瘤。在NSC中,H3.3-K27M导致干性和增殖基因的维持表达以及OPC程序的过早激活,从而共同可能导致肿瘤的发生。
附:英文原文
Title: H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model
Author: Daniel Haag, Norman Mack, Patricia Benites Goncalves da Silva, Britta Statz, Jessica Clark, Koji Tanabe, Tanvi Sharma, Natalie Jger, David T.W. Jones, Daisuke Kawauchi, Marius Wernig, Stefan M. Pfister
Issue&Volume: 2021-02-04
Abstract: Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstemwith currently no curative treatment available. The vast majority of DIPGs carry ahistone H3 mutation leading to a lysine 27-to-methionine exchange (H3K27M). We engineeredhuman induced pluripotent stem cells (iPSCs) to carry an inducible H3.3-K27M allelein the endogenous locus and studied the effects of the mutation in different disease-relevantneural cell types. H3.3-K27M upregulated bivalent promoter-associated developmentalgenes, 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 extentin oligodendrocyte progenitor cells (OPCs). Only NSCs gave rise to tumors upon inductionof 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 apremature activation of OPC programs that together may cause tumor initiation.
DOI: 10.1016/j.ccell.2021.01.005
Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00049-0
Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:38.585
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx
本期文章:《癌细胞》:Online/在线发表