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，约有 5000 例新发病例 在美国，0-14 岁儿童中每年诊断出的脑肿瘤中约有 17% 为高级别脑肿瘤。 神经胶质瘤（HGG）目前无法治愈，缺乏有效的治疗方法凸显了迫切需要。 最近揭示了大量实验证据，以确定基于机制的治疗方法。 H3.3-G34R——携带儿科 HGGs (pHGGs) 表现出高度基因组不稳定性和高水平表达 神经元标记物，表明与其他肿瘤相比，这些肿瘤代表 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。 使用新建立的基因工程小鼠模型（GEMM），我们发现了功能丧失突变。 证明癌前神经干细胞 (PM-NSC) 中的 H3.3-G34R 突变和 ATRX 缺失与 Trp53-/-背景可以强烈促进神经胶质瘤发生，这些肿瘤表现出人类的典型特征。 H3.3-G34R——含有pHGG，因此该GEMM为我们提供了研究分子的可靠工具 H3.3-G34R 突变和 ATRX 缺失协同作用的潜在机制和识别 我们发现 H3.3-G34R 突变会局部改变组蛋白修饰。 并在全球范围内导致 FoxD1 和 HoxA1 的高表达，这两种转录因子对于早期神经元至关重要 鉴于 FoxD1 和 HoxA1 的富集与神经胶质瘤的预后较差相关。 患者，他们为 pHGGs 提供了 2 个新的治疗靶点。此外，我们发现 ATRX 丢失会导致 ALT。 激活，这使得肿瘤细胞对其线粒体功能的扰动敏感。 通过观察，我们捕获了 H3.3-G34R 突变和 ATRX 丢失诱导的独特表观遗传特征 驱动神经胶质瘤发生并导致涉及端粒功能失调和受损的可靶向脆弱性 为了检验这一假设，我们计划 1) 确定 FoxD1 和 HoxA1 在 H3.3- 中的作用。 G34R 驱动的神经胶质瘤发生，2) 定义了 pHGG 中 ATRX 缺乏引起的治疗脆弱性，以及 3）阐明H3.3-G34R突变和ATRX缺失对表观遗传重编程的协同作用 所提出的研究的完成不仅将填补我们对 H3.3-G34R 的了解的空白。 ATRX 损失会改变表观基因组，从而导致正常的神经发育和神经胶质瘤发生，而且 - 更重要的是，有助于制定针对 pHGG 的治疗策略并提供 深入了解表观遗传调控在大脑发育和神经胶质瘤发生中的作用。