Role of the K27M histone mutation in midline gliomas initiated in oligodendrocyte progenitors

项目摘要 弥漫性中线胶质瘤(DMG)，包括弥漫性固有桥脑胶质瘤(DIPG)，是一种罕见的儿科肿瘤。 它发生在儿童的脑干中，是导致脑瘤儿童死亡的主要原因。这个 目前的治疗标准是放射治疗，这只能略微提高存活率。缺乏临床相关性的 模型是为患有DMG的儿童开发有效治疗的主要障碍。一种新的杂合子 在80%的DIPGs中，组蛋白H3.3/3.1存在Lys27Met(K27M)突变。然而， 组蛋白突变促进脑干胶质瘤发生的机制尚未完全阐明。 多条证据表明脑干中存在表达寡突胶质细胞的祖细胞(OPC) 可能是DIPG的起源细胞，尤其是携带H3.3K27M突变的亚型。因为 致癌基因突变的下游后果取决于肿瘤细胞的起源，关键是 建立和鉴定OPC起源的中线胶质瘤小鼠模型，以加速DIPG研究和 治疗方面的发展。在这里，我们建议研究H3.3K27M突变在一种新的DIPG中的作用 OPC启动中线肿瘤的小鼠模型。具体地说，我们将进行彻底的肿瘤生物学 和来自OPC的脑干肿瘤的分子特征，并进行比较分析 巢蛋白细胞来源的肿瘤。我们推测H3.3K27M在OPC中的表型和分子效应。 启动肿瘤将有别于巢蛋白启动的肿瘤，从而确定新的可操作的治疗方法 组蛋白突变的终点。因此，我们的研究将认证第一个具有免疫活性的小鼠模型 在OPC中发起的DIPG，为DIPG研究社区提供了一个新的平台，以执行机械和 翻译研究。阐明OPC中组蛋白突变的下游后果，以及 更好地了解其基于细胞的作用，将有助于为未来的临床前和 基于疾病分子基础的DIPG和其他中线胶质瘤的临床研究。

Project Summary Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), is a rare form of pediatric tumor that arises in the brainstem of children, and is the leading cause of death among children with a brain tumor. The current standard of care is radiotherapy, which only modestly improves survival. The lack of clinically relevant models is a major barrier to developing effective therapies for children with DMG. A novel heterozygous Lys27Met (K27M) mutation has been shown to occur in histones H3.3/3.1 in ~80% of DIPGs. However, the mechanisms by which the histone mutations promote brainstem gliomagenesis have not been fully elucidated. Several lines of evidence implicate Olig2-expressing (oligodendrocyte) progenitor cells (OPCs) in the brainstem as the likely cell-of-origin for DIPG, especially for the subtype bearing the H3.3K27M mutation. Because downstream consequences of oncogenic mutations are dependent on the tumor cell-of-origin, it is critical to develop and characterize a mouse model of midline gliomas initiated in OPCs to accelerate DIPG research and therapeutic development. Here, we propose to investigate the role of the H3.3K27M mutation in a novel DIPG mouse model where midline tumors are initiated in OPCs. Specifically, we will perform thorough tumor biologic and molecular characterization of brainstem tumors originating from OPCs, and perform a comparative analysis of Nestin cell-of-origin tumors. We hypothesize that the phenotypic and molecular effects of H3.3K27M in OPC- initiated tumors will be distinct from Nestin-initiated tumors, thus identifying novel therapeutically actionable endpoints of the histone mutation. Thus, our study will credential the first immunocompetent mouse model of DIPG initiated in OPCs, providing a novel platform to the DIPG research community to perform mechanistic and translational research. Elucidation of the downstream consequences of the histone mutation in OPCs, along with improved understanding of its cell-of-origin based effects, will help lay the foundation for future preclinical and clinical studies of DIPG and other midline gliomas based on the molecular underpinnings of the disease.