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: 10296014
• 负责人: Jian Hu
• 金额: $ 42.64万
• 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/10296014
• 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.

概述/文摘