Investigating the role of dysfunctional histone H3.3 in driving early neuronal development and pediatric high-grade gliomas

研究功能失调的组蛋白 H3.3 在驱动早期神经元发育和儿童高级别胶质瘤中的作用

• 批准号: 10416054
• 负责人: Jian Hu
• 金额: $ 29.85万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10416054
• 关键词: ATRX gene; Affect; Age; Alleles; Automobile Driving; Brain; Brain Neoplasms; Cells; Childhood; Childhood Brain Neoplasm; Childhood Glioma; Deposition; Development; Diagnosis; Disease; Ensure; Epigenetic Process; Exhibits; Gene Expression Profile; Genetic; Genetically Engineered Mouse; Genomic Instability; Glioma; Gliomagenesis; Goals; Histone H3; Histones; Human; Impairment; Knock-in; Knowledge; Lead; Malignant Neoplasms; Mediator of activation protein; Mitochondria; Modification; Molecular; Molecular Chaperones; Mutate; Mutation; Neurons; Oncogenic; Patients; Pediatric Neoplasm; Point Mutation; Prognosis; Reactive Oxygen Species; Role; Solid Neoplasm; Switch Genes; Testing; Therapeutic; Translations; United States; Up-Regulation; base; effective therapy; epigenetic regulation; epigenome; histone modification; in vivo Model; insight; loss of function mutation; mutant; neoplastic cell; nerve stem cell; neuroblast; neuron development; new therapeutic target; novel; novel therapeutic intervention; premalignant; prevent; telomere; therapeutic development; therapeutic target; tool; transcription factor; tumor

Summary Statement/Abstract Pediatric brain tumors are the most common solid tumors in children, with approximately 5000 new cases diagnosed per year in the United States. Around 17% of brain tumors in children age 0–14 years are high-grade gliomas (HGGs), which are currently incurable. The lack of effective treatments highlights the urgent need to identify mechanism-based therapeutic approaches. Substantial experimental evidence has recently revealed that H3.3-G34R–harboring pediatric HGGs (pHGGs) exhibit high genomic instability and high-level expression of neuronal markers, indicating that these tumors represent a distinct subtype of pHGG compared with other types, including the one with an H3.3-K27M mutation. More than 90% of H3.3-G34R gliomas also harbor ATRX loss-of-function mutations. Using a newly established genetically engineered murine model (GEMM), we demonstrated that H3.3-G34R mutation and ATRX deletion in premalignant neural stem cells (PM-NSCs) with the Trp53-/- background could strongly promote gliomagenesis. These tumors exhibit typical features of human H3.3-G34R–harboring pHGGs, so this GEMM provides us with a faithful tool for studying the molecular mechanisms underlying the synergistic effects of H3.3-G34R mutation and ATRX deletion and for identifying novel therapeutic targets. We have found that H3.3-G34R mutation changes histone modifications both locally and globally and leads to high expression of FoxD1 and HoxA1, transcription factors essential for early neuronal development. Given that enrichments of FoxD1 and HoxA1 are associated with worse prognosis in glioma patients, they provide 2 novel therapeutic targets for pHGGs. In addition, we found that ATRX loss leads to ALT activation, which makes tumor cells sensitive to perturbation of their mitochondrial function. On the basis of these observations, we hypothesize that distinctive epigenetic profiles induced by H3.3-G34R mutation and ATRX loss drive gliomagenesis and lead to targetable vulnerabilities involving dysfunctional telomeres and impaired mitochondrial activity. To test this hypothesis, we plan to 1) determine the roles of FoxD1 and HoxA1 in H3.3- G34R–driven gliomagenesis, 2) define the therapeutic vulnerability induced by ATRX deficiency in pHGGs, and 3) elucidate the synergistic effect of H3.3-G34R mutation and ATRX loss on epigenetic reprogramming in gliomas. The completion of the proposed studies will not only fill the gaps in our knowledge of how H3.3-G34R and ATRX loss change the epigenome to lead to normal neuronal development and gliomagenesis, but also— and more importantly—contribute to the development of therapeutic strategies that target pHGGs and provide insights into the role of epigenetic regulation in brain development and gliomagenesis.

摘要声明/摘要 小儿脑肿瘤是儿童最常见的实体瘤，大约5000例新病例 在美国每年被诊断出。 0-14岁儿童中约有17％的脑肿瘤是高级 胶质瘤（HGGS），目前无法治愈。缺乏有效的治疗凸显了迫切需要 确定基于机制的治疗方法。大量的实验证据最近揭示了 H3.3-G34R - 河晶儿科HGGS（PHGGS）暴露了高基因组不稳定性和高级表达 神经元标记物的，表明这些肿瘤代表了PHGG的独特亚型 类型，包括具有H3.3-K27M突变的类型。超过90％的H3.3-G34R神经胶质瘤也含有ATRX 功能丧失突变。使用新建立的基因工程鼠模型（GEMM），我们 证明具有前神经元干细胞（PM-NSC）的H3.3-G34R突变和ATRX缺失 TRP53 - / - 背景可以强烈促进神经胶质作用。这些肿瘤暴露了人类的典型特征 H3.3-G34R - harboring phggs，因此该GEMM为我们提供了一个忠实的工具来研究分子 H3.3-G34R突变和ATRX缺失的协同作用的基础机制，用于识别 新型热目标。我们发现H3.3-G34R突变改变了组蛋白的修饰 在全球范围内，并导致FOXD1和HOXA1的高表达，对早期神经元必不可少的转录因子 发展。鉴于FOXD1和HOXA1的富集与神经胶质瘤的预后较差有关 患者，他们为PHGG提供了2个新型的治疗靶标。此外，我们发现ATRX损失导致ALT 激活，这使肿瘤细胞对其线粒体功能的扰动敏感。根据这些 观察结果，我们假设H3.3-G34R突变和ATRX丢失引起的独特表观遗传谱 驱动神经胶质作用并导致涉及功能障碍和受损的靶向漏洞 线粒体活性。为了检验该假设，我们计划1）确定FOXD1和HOXA1在H3.3-中的作用。 G34R驱动的神经胶质作用，2）定义由ATRX缺乏引起的治疗脆弱性，而PHGGS和 3）阐明H3.3-G34R突变和ATRX损失对表观遗传重编程的协同作用 神经胶质瘤。拟议的研究的完成不仅会填补我们对H3.3-G34R的知识的差距 ATRX的损失改变了表观基因组，导致正常的神经元发育和神经胶质作用，但也可以 更重要的是 - 归因于针对PHGG的理论策略的制定并提供 对表观遗传调节在脑发育和胶质敏作中的作用的见解。