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: 10552535
• 负责人: Kaitlin Budd
• 金额: $ 4.28万
• 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/10552535
• 关键词: Anaplastic astrocytoma; Brain; Brain Stem; Brain Stem Neoplasms; Cessation of life; Child; Childhood; Childhood Glioma; Data; Dependence; Development; Diffuse intrinsic pontine glioma; Embryo; Epigenetic Process; Frequencies; Gene Expression; Genetic Transcription; Genetically Engineered Mouse; Glioma; Gliomagenesis; Growth; H3 K27M mutation; Histone H3; Human; Investigative Techniques; Knock-in; Knock-in Mouse; Label; Laboratories; Literature; Location; Maintenance; Malignant Childhood Neoplasm; Mediating; Modeling; Molecular; Molecular Target; Mus; Mutation; Neurobiology; Oligodendroglia; Oncogenic; Pathogenesis; Patients; Phenotype; Physiological; Population; Prognosis; Prosencephalon; Quantitative Reverse Transcriptase PCR; Radiation; Research; Research Personnel; Resistance; Role; Structure; Survival Rate; TP53 gene; Therapeutic; Training; Unresectable; density; diffuse midline glioma; glial cell development; gliogenesis; hindbrain; human RNA sequencing; in vivo; insight; mouse model; nerve stem cell; neurodevelopment; new therapeutic target; novel therapeutics; oligodendrocyte myelination; oligodendrocyte precursor; oncohistone; patient derived xenograft model; postnatal development; progenitor; programs; regional difference; single-cell RNA sequencing; spatiotemporal; stem; stemness; therapeutic development; transcriptomics; tumor; tumor growth; tumor initiation; tumorigenesis

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： 弥漫性内在庞然神经胶质瘤（DIPG）是一种无法治愈的高级神经胶质瘤，主要在脑干中产生 年幼的孩子。 DIPG 2年生存率<10％，由于其无法切除的肿瘤位置和对 辐射和可用的治疗学。这强调需要更好地理解基础 DIPG的发病机理，以识别新的治疗性脆弱性。组蛋白H3 LYS27MET（K27M）突变是一个 统一的分子特征观察到约80％的DIPG和小儿弥漫性中线神经胶质瘤（DMG）。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的优势。理解K27M的区域性 它的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的老鼠模型，该模型带有 将K27M的条件敲入内源性H3F3A基因座，该基因座允许在A中研究突变 生理和发展相关的方式。使用此模型，我们显示了K27M与PDGFRA合作 在脑干和后脑位置选择性地驱动自发神经胶质作用的激活和p53损失。 K27M导致抑制性H3K27me3的急剧损失，但仅基因表达相关的特定变化 致神经发育。人类K27M DIPG的单细胞RNA-seq揭示了少突胶质前体（OPC） 是DIPG中存在的主要增殖和类似茎状的种群。我们还表明了 K27M在患者衍生的异种移植物中诱导少突胶质细胞（OL）分化特征，降低了茎 签名并减少增殖和肿瘤生长。总的来说，这些研究表明K27M在区域中的作用 脑干肿瘤发生的选择性以及OL分化改变，促进了OPC样状态。然而， 关于K27M和DIPG仍然存在许多问题。为什么在脑干和 中线小儿神经胶质瘤？仅K27M的致癌作用和机制是什么？我将利用我们的K27M 敲入小鼠剖析H3 K27M对胶质神经胶质发育和体内肿瘤发生的区域影响（AIM 1） 并评估少突胶质细胞中的区域K27M介导的表观遗传和转录组失调 开发以识别K27M DIPG依赖性（AIM 2）。通过完成这些研究，我们将获得 洞悉K27M的分子机制和时空环境，这些机制破坏了发展和 促进肿瘤发生，这将有助于指导治疗性发育以针对分子程序 涉及的区域和细胞状态。