Regional selectivity of oncohistone H3K27M on glial development and glioma pathogenesis

癌组蛋白 H3K27M 对神经胶质发育和神经胶质瘤发病机制的区域选择性

• 批准号: 10315763
• 负责人: Kaitlin Budd
• 金额: $ 4.2万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315763
• 关键词: Regional; selectivity; oncohistone; H3K27M; glial

Abstract: Diffuse intrinsic pontine glioma (DIPG) is an incurable high-grade glioma arising in the brainstem primarily in younger children. DIPG 2-year survival rate is <10% due to its unresectable tumor location and resistance to radiation and available therapeutics. This emphasizes the need for better understanding of the underlying pathogenesis of DIPG to identify new therapeutic vulnerabilities. Histone H3 Lys27Met (K27M) mutations are a unifying molecular feature observed ~80% of DIPGs and pediatric diffuse midline gliomas (DMG). The high frequency of K27M and their exclusivity to childhood DIPG and DMG suggests K27M has a unique selective advantage in a distinct spatiotemporal setting for tumorigenesis. Understanding the regional selectively of K27M and its phenotypic and molecular effects will further elucidate oncogenic mechanisms and help identify new and better treatment options. The Baker laboratory developed a genetically engineered mouse model harboring a conditional knock-in of K27M into the endogenous H3f3a locus which allows the mutation to be studied in a physiologically and developmentally relevant manner. With this model, we showed K27M cooperates with Pdgfra activation and or p53 loss to drive spontaneous gliomagenesis selectively in brainstem and hindbrain locations. K27M causes dramatic loss of the repressive H3K27me3 but only specific changes in gene expression related to neurodevelopment. Single-cell RNA-seq of human K27M DIPGs reveals oligodendrocyte precursors (OPC) are the main proliferative and stem-like population present in DIPGs. We have also showed that depletion of K27M in patient-derived xenografts induces oligodendrocyte (OL) differentiation signatures, decreases stemness signatures, and reduces proliferation and tumor growth. In total, these studies indicate a role for K27M in regional selectivity of brainstem tumorigenesis along with altered OL differentiation, promoting OPC-like state. However, many questions still remain regarding K27M and DIPG. Why is K27M found almost exclusively in brainstem and midline pediatric glioma? What are the oncogenic effects and mechanisms of K27M alone? I will utilize our K27M knock-in mice to dissect the regional effects of H3 K27M on glial development and tumorigenesis in vivo (Aim 1) and evaluate the regional K27M-mediated epigenetic and transcriptomic dysregulation in oligodendrocyte development to identify K27M DIPG dependencies (Aim 2). Through completion of these studies, we will gain insights into the molecular mechanisms and spatiotemporal context of K27M that disrupt development and promote tumorigenesis which will help to direct therapeutic development to target the molecular programs involved that are specific to region and cellular state.

抽象的： 弥漫性内在桥脑胶质瘤（DIPG）是一种无法治愈的高级胶质瘤，主要发生在脑干中 年幼的孩子。由于其不可切除的肿瘤位置和耐药性，DIPG 2 年生存率 <10% 放射和可用的治疗方法。这强调需要更好地理解底层 DIPG 的发病机制以确定新的治疗漏洞。组蛋白 H3 Lys27Met (K27M) 突变是 约 80% 的 DIPG 和儿童弥漫性中线胶质瘤 (DMG) 观察到统一的分子特征。高 K27M 的频率及其对儿童 DIPG 和 DMG 的排他性表明 K27M 具有独特的选择性 在肿瘤发生的独特时空环境中具有优势。了解K27M的区域选择性 其表型和分子效应将进一步阐明致癌机制，并有助于识别新的和 更好的治疗选择。贝克实验室开发了一种基因工程小鼠模型，其中含有 将 K27M 条件性敲入内源 H3f3a 基因座，从而可以在 生理和发育相关的方式。通过这个模型，我们展示了K27M与Pdgfra的合作 激活和/或 p53 丢失选择性地驱动脑干和后脑位置的自发神经胶质瘤发生。 K27M 导致抑制性 H3K27me3 的显着丧失，但仅导致相关基因表达的特定变化 对神经发育。人类 K27M DIPG 的单细胞 RNA 测序揭示了少突胶质细胞前体 (OPC) 是 DIPG 中存在的主要增殖性和干状群体。我们还表明，耗尽 患者来源的异种移植物中的 K27M 诱导少突胶质细胞 (OL) 分化特征，降低干性 特征，并减少增殖和肿瘤生长。总的来说，这些研究表明 K27M 在区域性中的作用 脑干肿瘤发生的选择性以及 OL 分化的改变，促进 OPC 样状态。然而， 关于 K27M 和 DIPG 仍然存在许多问题。为什么 K27M 几乎只存在于脑干中 小儿中线胶质瘤？ K27M 单独使用的致癌作用和机制是什么？我将使用我们的 K27M 敲入小鼠剖析 H3 K27M 对体内神经胶质发育和肿瘤发生的区域影响（目标 1） 并评估少突胶质细胞中 K27M 介导的区域表观遗传和转录组失调 开发以确定 K27M DIPG 依赖性（目标 2）。通过完成这些研究，我们将获得 深入了解 K27M 扰乱发育和发育的分子机制和时空背景 促进肿瘤发生，这将有助于指导针对分子程序的治疗开发 涉及特定于区域和细胞状态的。