德国海德堡大学Stefan M. Pfister、美国斯坦福大学Marius Wernig等研究人员合作发现，H3.3-K27M在人类iPSC衍生的模型中可驱动神经干细胞特异性的神经胶质瘤形成。这一研究成果于2021年2月4日在线发表在国际学术期刊《癌细胞》上。

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