Role of the K27M histone mutation in midline gliomas initiated in oligodendrocyte progenitors

K27M 组蛋白突变在少突胶质细胞祖细胞中引发的中线神经胶质瘤中的作用

基本信息

批准号：
10058297
负责人：
Oren Josh Becher
金额：
$ 19.13万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058297
关键词：
Affect Alleles Apoptosis Biological Birds Brain Brain Neoplasms Brain Stem Brain Stem Neoplasms CDKN2A gene Cause of Death Cells ChIP-seq Child Childhood Childhood Brain Neoplasm Clinical Research Clinical Trials Communities Comparative Study Complex Development Diagnosis Diffuse Diffuse intrinsic pontine glioma Disease Foundations Future Gene Activation Gene Combinations Gene Expression Gene Mutation Gene Targeting Gene-Modified Genes Genetic Genetic Transcription Genetically Engineered Mouse Glioma Gliomagenesis Goals Health Histone H3 Histones Human Immunocompetent In Vitro Knowledge Malignant neoplasm of brain Methylation Mission Modeling Molecular Molecular Biology Mutation National Institute of Neurological Disorders and Stroke Neonatal Oncogenic Pathologic Pediatric Neoplasm Phenotype Platelet-Derived Growth Factor Polycomb Property Public Health Radiation therapy Research Research Proposals Role Study models System TP53 gene Therapeutic Translational Research Tumor Biology Up-Regulation Western Blotting angiogenesis anticancer research base cell motility cell type clinically relevant combat comparative effective therapy genetic signature improved in vivo innovation mouse model neonatal mice neoplastic cell nervous system disorder nestin protein neuron development novel novel strategies novel therapeutics oligodendrocyte progenitor overexpression preclinical study preclinical trial progenitor research and development self-renewal standard of care stem cells therapeutic development transcription factor transcriptome sequencing tumor tumor growth

项目摘要

Project Summary Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), is a rare form of pediatric tumor that arises in the brainstem of children, and is the leading cause of death among children with a brain tumor. The current standard of care is radiotherapy, which only modestly improves survival. The lack of clinically relevant models is a major barrier to developing effective therapies for children with DMG. A novel heterozygous Lys27Met (K27M) mutation has been shown to occur in histones H3.3/3.1 in ~80% of DIPGs. However, the mechanisms by which the histone mutations promote brainstem gliomagenesis have not been fully elucidated. Several lines of evidence implicate Olig2-expressing (oligodendrocyte) progenitor cells (OPCs) in the brainstem as the likely cell-of-origin for DIPG, especially for the subtype bearing the H3.3K27M mutation. Because downstream consequences of oncogenic mutations are dependent on the tumor cell-of-origin, it is critical to develop and characterize a mouse model of midline gliomas initiated in OPCs to accelerate DIPG research and therapeutic development. Here, we propose to investigate the role of the H3.3K27M mutation in a novel DIPG mouse model where midline tumors are initiated in OPCs. Specifically, we will perform thorough tumor biologic and molecular characterization of brainstem tumors originating from OPCs, and perform a comparative analysis of Nestin cell-of-origin tumors. We hypothesize that the phenotypic and molecular effects of H3.3K27M in OPC- initiated tumors will be distinct from Nestin-initiated tumors, thus identifying novel therapeutically actionable endpoints of the histone mutation. Thus, our study will credential the first immunocompetent mouse model of DIPG initiated in OPCs, providing a novel platform to the DIPG research community to perform mechanistic and translational research. Elucidation of the downstream consequences of the histone mutation in OPCs, along with improved understanding of its cell-of-origin based effects, will help lay the foundation for future preclinical and clinical studies of DIPG and other midline gliomas based on the molecular underpinnings of the disease.

项目摘要弥漫性中线神经胶质瘤（DMG），包括弥漫性内在蓬托胶质瘤（DIPG），是一种罕见的小儿肿瘤形式这是在儿童的脑干中产生的，是脑肿瘤儿童死亡的主要原因。这当前的护理标准是放疗，只能适度提高生存率。缺乏临床相关的模型是开发DMG儿童有效疗法的主要障碍。一种新颖的杂合 Lys27mET（K27M）突变已显示出在〜80％的DIPGS中H3.3/3.1中发生。但是，尚未完全阐明组蛋白突变促进脑干神经胶作用的机制。几条证据暗示了表达寡聚的（少突胶质细胞）祖细胞（OPC）的脑干作为DIPG的可能细胞细胞，特别是对于带有H3.3K27M突变的亚型。因为致癌突变的下游后果取决于肿瘤细胞 - 至关重要开发和表征在OPC中启动的中线胶质瘤的小鼠模型，以加速DIPG研究和治疗发展。在这里，我们建议研究H3.3K27M突变在新型DIPG中的作用在OPC中启动中线肿瘤的小鼠模型。具体而言，我们将执行彻底的肿瘤生物学源于OPC的脑干肿瘤的分子表征，并进行比较分析巢蛋白细胞肿瘤。我们假设H3.3K27M在OPC中的表型和分子作用引发的肿瘤将与巢蛋白引起的肿瘤不同，从而鉴定出新颖的治疗作用组蛋白突变的终点。因此，我们的研究将凭借首个免疫功能的小鼠模型 DIPG在OPC中启动，为DIPG研究社区提供了一个新颖的平台，以执行机械和翻译研究。阐明OPC中组蛋白突变的下游后果，以及对其基于原始细胞的影响的了解的了解将有助于未来的临床前和基于该疾病的分子基础，对DIPG和其他中线神经胶质瘤的临床研究。