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.

弥漫性内源性脑桥胶质瘤 (DIPG) 是一种侵袭性儿童脑干肿瘤，目前尚无治愈性治疗方法。绝大多数 DIPG 携带组蛋白 H3 突变，导致赖氨酸 27 到蛋氨酸交换 (H3K27M)。我们设计了人类诱导多能干细胞 (iPSC)，使其在内源性基因座中携带可诱导的 H3.3-K27M 等位基因，并研究了突变对不同疾病相关神经细胞类型的影响。H3.3-K27M 上调二价启动子相关发育基因，在不同细胞类型中产生不同结果。虽然对 iPSC 是致命的，但 H3.3-K27M 增加了神经干细胞 (NSC) 的增殖，并在较小程度上增加了少突胶质祖细胞 (OPC)。只有 NSCs 在 H3.3-K27M 和TP53 的诱导下产生肿瘤在重现人类 DIPG 的原位异种移植模型中失活。在 NSC 中，H3.3-K27M 导致干细胞和增殖基因的维持表达以及 OPC 程序的过早激活，这些共同可能导致肿瘤发生。