A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M.
A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M.
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弥漫性中线神经胶质瘤（DMG）是一种主要发生于儿童的致命性脑肿瘤。大多数 DMG 的组蛋白 H3 中含有 K27M 突变。脑干中的少突胶质祖细胞 (OPC) 是 DMG 的候选起源细胞，但目前还没有以 OPC 启动的 DMG 基因工程小鼠模型。在这里，我们使用 RCAS/Tv-a 禽类逆转录病毒系统在新生小鼠脑干中表达 Olig2 的祖细胞和表达 Nestin 的祖细胞中产生 DMG。 PDGF-A 或 PDGF-B 过度表达以及 p53 缺失，导致两种模型中均产生神经胶质瘤。与 Nestin+ 细胞中的 H3.3WT 相比，H3.3K27M 的外源过表达对肿瘤潜伏期和肿瘤细胞增殖有显着影响，但在 Olig2+ 细胞中则不然。此外，在 PDGF-A 和 PDGF-B 驱动的模型中，Olig2+ 细胞中启动的 DMG 中 H3.3K27M 阳性细胞的比例显着低于 Nestin+ 细胞，这表明当 Olig2+ 细胞中启动肿瘤发生时，对 H3.3K27M 的需求减少。 RNA测序分析显示，H3.3K27M肿瘤中的差异表达基因在Olig2;PDGF-B、Olig2;PDGF-A和Nestin;PDGF-A模型之间不重叠。 PDGFA 肿瘤的 GSEA 分析证实，H3.3K27M 的转录效应是细胞源依赖性的，当 Olig2 标记源细胞时，H3.3K27M 促进上皮间质转化 (EMT) 和血管生成，而当 Nestin 标记源细胞时，H3.3K27M 抑制 EMT 和血管生成。我们确实观察到与 H3.3K27M 的一些重叠促进了两个模型中 TNFA_Signaling_Via_NFKB 的负富集。我们的研究表明，H3.3K27M 的致瘤作用具有细胞来源依赖性，H3.3K27M 在 Nestin+ 细胞中比 Olig2+ 细胞更具致癌性。我们描述了一种在新生儿 Olig2+ 祖细胞中启动的具有免疫功能的 DIPG 小鼠模型。致癌组蛋白 H3.3K27M 在 Olig2+ 细胞中的致癌性低于 Nestin+ 细胞，并且以细胞来源依赖性方式改变肿瘤转录组。
Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells‐of‐origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv‐a avian retroviral system to generate DMG in Olig2‐expressing progenitors and Nestin‐expressing progenitors in the neonatal mouse brainstem. PDGF‐A or PDGF‐B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M‐positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF‐A and PDGF‐B‐driven models, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. RNA‐sequencing analysis revealed that the differentially expressed genes in H3.3K27M tumors were non‐overlapping between Olig2;PDGF‐B, Olig2;PDGF‐A, and Nestin;PDGF‐A models. GSEA analysis of PDGFA tumors confirmed that the transcriptomal effects of H3.3K27M are cell‐of‐origin dependent with H3.3K27M promoting epithelial‐to‐mesenchymal transition (EMT) and angiogenesis when Olig2 marks the cell‐of‐origin and inhibiting EMT and angiogenesis when Nestin marks the cell‐of‐origin. We did observe some overlap with H3.3K27M promoting negative enrichment of TNFA_Signaling_Via_NFKB in both models. Our study suggests that the tumorigenic effects of H3.3K27M are cell‐of‐origin dependent, with H3.3K27M being more oncogenic in Nestin+ cells than Olig2+ cells. We describe an immunocompetent mouse model of DIPG initiated in neonatal Olig2+ progenitors. The oncohistone H3.3K27M is less oncogenic in Olig2+ cells than Nestin+ cells, and alters the tumor transcriptome in a cell‐of‐origin dependent manner.
影响因子：
3.1
作者：
Walker AS;Goings GE;Kim Y;Miller RJ;Chenn A;Szele FG
通讯作者：
Szele FG