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.

摘要： 弥漫性桥脑胶质瘤(DIPG)是一种发生于脑干的不可治愈的高级别胶质瘤，主要发生于 年龄更小的孩子。DIPG的2年存活率为10%，原因是其无法切除的肿瘤位置和对 辐射和可用的治疗方法。这强调了需要更好地理解潜在的 DIPG的发病机制以确定新的治疗脆弱性。组蛋白H3 Lys27Met(K27M)突变是一种 结合分子特征观察到约80%的DIPG和儿童弥漫性中线胶质瘤(DMG)。高潮 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。有选择地理解K27M的地区性 它的表型和分子效应将进一步阐明致癌机制，并有助于发现新的和 更好的治疗方案。贝克实验室开发了一种基因工程小鼠模型，该模型含有一种 K27M有条件地敲入内源性H3F3A基因座，使突变能够在 生理上和发育上相关的方式。在这个模型中，我们展示了K27M与PDGFRA的合作 激活和/或P53的缺失选择性地驱动脑干和后脑部位的自发胶质瘤形成。 K27M导致抑制性H3K27me3的急剧丧失，但只导致相关基因表达的特定变化 神经发育。人K27M DIPGs单细胞RNA序列揭示少突胶质前体细胞(OPC) 是DIPGs中存在的主要增殖性和干状种群。我们也已经表明， 患者来源的异种移植中的K27M诱导少突胶质细胞(OL)分化特征，减少茎 签名，并减少增殖和肿瘤生长。总而言之，这些研究表明，K27M在区域中发挥了作用 随着OL分化的改变，脑干肿瘤发生的选择性，促进了OPC样状态。然而， 关于K27M和DIPG，许多问题仍然存在。为什么K27M几乎只存在于脑干和 中线儿童神经胶质瘤？K27M单独的致癌作用和机制是什么？我会用我们的K27M 敲入小鼠解剖H3K27M对胶质细胞发育和体内肿瘤形成的局部影响(目标1) 并评估K27M介导的少突胶质细胞局部表观遗传和转录异常。 开发以确定K27M DIPG依赖关系(目标2)。通过完成这些研究，我们将获得 对K27M破坏发育和发育的分子机制和时空背景的洞察 促进肿瘤的发生，这将有助于指导针对分子程序的治疗开发 涉及到特定于区域和细胞状态的。