MECHANISMS OF POL II ELONGATION IN DIFFUSE MIDLINE GLIOMA

弥漫性中线胶质瘤中 POL II 伸长的机制

基本信息

批准号：
10564343
负责人：
Jamie N. Anastas
金额：
$ 47.3万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10564343
关键词：
Ablation Adult Antineoplastic Agents Automobile Driving Binding Binding Sites Brain Neoplasms CRISPR screen Cells Chemicals Child Childhood Chromatin Chromatin Structure Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Complex DNA Polymerase II Data Defect Dependence Development Diagnosis Diffuse Diffuse intrinsic pontine glioma Disease Elongation Factor Exhibits Gene Abnormality Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Genomics Glioma Gliomagenesis Goals Growth H3 K27M mutation Histone H3 Histones Investigation Knock-out Knowledge Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Measures Molecular Mus Mutation Normal Cell Normal tissue morphology Oncogenes Oncogenic Output Pathway interactions Patients Pattern Pharmaceutical Preparations Polymerase Pontine structure Proliferating Proteins RNA Polymerase II Regulation Regulator Genes Regulatory Pathway Research Role Somatic Mutation Transcription Elongation Tumor Suppressor Proteins VHL protein Von Hippel-Lindau Tumor Suppressor Protein Work Xenograft Model Xenograft procedure brain tissue cancer cell cancer therapy cell type chromatin modification diffuse midline glioma effective therapy elongin elongin B epigenome genetic regulatory protein genome-wide improved inhibitor insight mouse model mutant next generation sequencing nonsynonymous mutation novel overexpression pre-clinical programs targeted treatment tissue culture transcriptome sequencing transcriptomics treatment strategy tumor tumor growth tumor initiation tumor progression tumorigenesis

项目摘要

Project Summary/Abstract Diffuse midline gliomas (DMGs) are aggressive brain tumors in both children and adults with no effective therapies. Over 80% of pediatric DMG and a majority of adult DMG harbor non-synonymous mutations in histone H3 (H3.3K27M and H3.1K27M), which dysregulate chromatin and result in aberrant Pol II transcription in brain tumors compared to normal tissue. Aberrant transcription is not only a cause of tumorigenesis, but also a druggable vulnerability as there are multiple studies investigating the utility of Pol II and epigenome-targeting drugs for the treatment of cancer. Despite the initial promise of compounds targeting transcriptional dysregulation as potential cancer therapies, none of the drugs under investigation in clinical trials have improved DMG patient survival thus far. A critical barrier to the discovery of more effective and less toxic therapies for DMG is our lack of functional knowledge regarding the molecular pathways connecting H3K27M mutant histones to tumor initiation and progression. We have recently conducted CRISPR screens identifying multiple regulators of Pol II transcriptional elongation as genetic dependencies in H3K27M mutant cells, including Elongin B (ELOB), and its binding partner, the Von Hippel-Lindau disease protein and tumor suppressor, VHL. Further preliminary studies reveal that genetic ablation of ELOB alters the chromatin binding patterns of H3K27M mutant histones, and disrupts DMG gene expression. These data support our overall hypothesis that H3K27M mutant histones enlist the activity of specific gene regulatory complexes to induce Pol II transcriptional deregulation and trigger DMG tumorigenesis. Our broad, long-term goal is to identity genes and molecular pathways driving glioma-specific transcriptional programs and to determine their roles in brain cancer development and progression. We propose the following specific aims: 1) Establish roles for Pol II elongation regulators in pre-clinical mouse models of DMG and investigate genetic interactions between the elongation machinery and H3K27M; 2) Apply cutting edge next generation sequencing analyses to dissect mechanisms of crosstalk between Pol II regulatory proteins and H3K27M and determine their roles in promoting abnormal gene regulation in DMG; 3) Investigate an unexpected oncogenic role for Elongin/VHL complexes in promoting malignant gene expression patterns and DMG tumor growth. The significance of this work is that these studies will reveal new insights into how H3K27M oncogenic histones co-opt specific Pol II regulators to promote tumorigenesis, and will uncover molecular mechanisms driving aberrant chromatin and gene regulation in DMG and other cancers.

项目摘要/摘要弥漫性中线神经胶质瘤（DMG）是儿童和成人均具有侵略性的脑肿瘤，无效疗法。多80％的小儿DMG和大多数成年DMG港口非同义突变在组蛋白中 H3（H3.3K27M和H3.1K27M），它失调染色质并导致大脑中异常的POL II转录肿瘤与正常组织相比。异常转录不仅是肿瘤发生的原因，而且是可吸毒的脆弱性，因为有多项研究调查了POL II和表观基因组靶向的效用治疗癌症的药物。尽管最初的靶向转录失调的化合物有望作为潜在的癌症疗法，在临床试验中没有研究的药物都没有改善DMG患者到目前为止的生存。我们缺乏发现对DMG发现更有效和毒性疗法的关键障碍有关将H3K27M突变组蛋白连接到肿瘤的分子途径的功能知识启动和进展。我们最近进行了CRISPR屏幕，以识别Pol II的多个调节器转录伸长作为H3K27M突变细胞中的遗传依赖性，包括源自元素B（ELOB），IT 结合伴侣，von Hippel-Lindau疾病蛋白和抑制肿瘤VHL。进一步的初步研究揭示ELOB的遗传消融会改变H3K27M突变组蛋白的染色质结合模式，并改变破坏DMG基因表达。这些数据支持我们的总体假设，即H3K27M突变体组蛋白招募特定基因调节复合物的活性诱导POL II转录放松管制并触发DMG 肿瘤发生。我们广泛的长期目标是识别基因和驱动胶质瘤特异性的分子途径转录程序并确定其在脑癌发展和进展中的作用。我们建议以下具体目的：1）在临床前小鼠模型的模型 DMG并研究伸长机械与H3K27M之间的遗传相互作用； 2）施加尖端下一代测序分析以在Pol II调节蛋白和 H3K27M并确定它们在促进DMG中异常基因调控方面的作用； 3）调查意外力素/VHL复合物在促进恶性基因表达模式和DMG肿瘤中的致癌作用生长。这项工作的意义在于，这些研究将揭示有关H3K27M致癌的新见解组蛋白选择特定的POL II调节剂以促进肿瘤发生，并将发现分子机制在DMG和其他癌症中驱动异常染色质和基因调节。