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: 10626949
• 负责人: Kaitlin Budd
• 金额: $ 4.37万
• 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/10626949
• 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; 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; Proliferating; Prosencephalon; Quantitative Reverse Transcriptase PCR; Radiation; Research; Research Personnel; Resistance; Role; Structure; Survival Rate; TP53 gene; Techniques; Therapeutic; Training; Unresectable; density; diffuse midline glioma; glial cell development; gliogenesis; hindbrain; human RNA sequencing; in vivo; insight; mouse model; myelination; nerve stem cell; neurodevelopment; new therapeutic target; novel therapeutics; 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.

摘要： 弥漫性内在脑桥胶质瘤（DIPG）是一种无法治愈的高级别胶质瘤，主要发生在脑干， 更小的孩子。DIPG的2年生存率<10%，这是由于其不可切除的肿瘤位置和对化疗的抵抗。 放射和可用的治疗方法。这就强调需要更好地了解 DIPG的发病机制，以确定新的治疗漏洞。组蛋白H3 Lys 27 Met（K27 M）突变是一种 在约80%的DIPG和小儿弥漫性中线胶质瘤（DMG）中观察到统一的分子特征。高 K27 M的频率及其对儿童DIPG和DMG的排他性表明K27 M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。对K27 M区域选择性的认识 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 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， 将K27 M有条件地敲入内源性H3 f3 a基因座，这允许在一个突变研究中研究突变。 生理和发育相关的方式。通过该模型，我们展示了K27 M与Pdgfra的协同工作 激活和/或p53损失，以选择性地驱动脑干和后脑位置中的自发性胶质瘤形成。 K27 M导致抑制性H3 K27 me 3的显著丧失，但仅在基因表达相关的特异性变化 到神经发育。人K27 M DIPG的单细胞RNA-seq揭示了少突胶质细胞前体（OPC） 是DIPG中存在的主要增殖和干细胞样群体。我们还发现， 患者来源的异种移植物中的K27 M诱导少突胶质细胞（OL）分化特征，降低干性 标记，并减少增殖和肿瘤生长。总的来说，这些研究表明K27 M在区域性 脑干肿瘤发生的选择性沿着OL分化的改变，促进OPC样状态。然而，在这方面， 关于K27 M和DIPG仍然存在许多问题。为什么K27 M几乎只存在于脑干， 中线小儿神经胶质瘤K27 M单独的致癌作用和机制是什么？我将使用我们的K27 M 基因敲入小鼠，以剖析H3 K27 M对体内胶质细胞发育和肿瘤发生的局部影响（目的1） 并评估区域K27 M介导的少突胶质细胞表观遗传和转录组失调 开发以识别K27 M DIPG依赖性（目标2）。通过完成这些研究，我们将获得 深入了解K27 M破坏发育的分子机制和时空背景， 促进肿瘤发生，这将有助于指导治疗开发以靶向分子程序 涉及特定区域和细胞状态。