Oncohistones: Role of Histone H3 Mutations in the Oncogenesis of Pediatric Cancers

肿瘤组蛋白：组蛋白 H3 突变在小儿癌症发生中的作用

基本信息

批准号：
9217804
负责人：
CHARLES DAVID ALLIS
金额：
$ 3.43万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-09 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9217804
关键词：
20 year old Address Adolescent Affect Animal Model Arginine Astrocytoma Automobile Driving Biochemical Biochemical Reaction Biochemistry Biological Assay Biology Bone neoplasms Brain Neoplasms Cancer Biology Cancer Model Cell Line Cells Cessation of life ChIP-seq Charge Chemicals Chemistry Child Childhood Childhood Brain Neoplasm Childhood Glioma Chondroblastoma Chromatin Chromatin Structure Clinical Complex DNA Modification Process Defect Deposition Development Diagnosis Disease Dissection Engineering Environment Enzymes Epigenetic Process Experimental Models Frequencies Future Gene Expression Genes Genetic Genetic Engineering Genome Genomic approach Genomics Glycine Goals Histone Code Histone H3 Histones Human Immunohistochemistry In Vitro Investigation Knowledge Lead Life Link Lysine Maintenance Malignant Bone Neoplasm Malignant Childhood Neoplasm Malignant Neoplasms Mass Spectrum Analysis Mesenchymal Methionine Methods Methylation Missense Mutation Modeling Molecular Multipotent Stem Cells Mus Mutate Mutation Nucleosomes Oncogenic Pathogenesis Pathway interactions Patients Pattern Play Polycomb Pre-Clinical Model Primary Neoplasm Proteins Proteomics Reagent Recurrence Resources Role Sampling Signal Pathway Somatic Mutation System Technology Testing Therapeutic Translations Valine Variant Work Xenograft procedure actionable mutation analytical tool base big gastrin cancer genetics cancer type design effective therapy epigenome epigenomics facsimile genetically modified cells genome-wide histone methyltransferase histone modification human disease improved in vivo innovation insight member mouse model multidisciplinary mutant neoplastic cell novel novel strategies novel therapeutics programs reconstitution repaired theories therapeutic development tool transcriptome transcriptome sequencing tumor tumor progression tumorigenesis young adult

项目摘要

DESCRIPTION (provided by applicant): Genome-wide sequencing technologies have allowed an unprecedented discovery of somatic mutations in epigenetic modifiers in human cancers, providing mechanistic links between cancer epigenomes and genetic alterations. The collective number of oncogenic activating mutations in epigenetic regulators has led to the emerging view of "driver mutations" underlying cancer epigenomes. Nowhere is this better illustrated than with recent findings of high-frequency missense mutations in core histones, such as histone H3 lysine 27 to methionine (H3K27M) and glycine 34 to arginine/valine (G34R/V) mutations in pediatric gliomas, and H3K36M mutations in pediatric chondroblastomas, particularly aggressive cancers that remain poorly understood and for which there are no effective therapies. Our biochemical studies suggest that the 'K-to-M' mutant histones can inhibit the enzymatic activity of responsible histone methyltransferases (HMTs), such as Ezh2 for H3K27 methylation, and SETD2 for H3K36 methylation. Oddly, histone mutations and HMT mutations are never found in the same type of cancer. These observations lead us to hypothesize that H3 'K-to-M' mutations play distinct functions beyond just inactivation of HMTs, which may be key to the lineage-specific pathogenesis of the respective cancers. Here, we propose multidisciplinary and integrative approaches, using genetics (cell line and mouse models), epigenetics (ChIP-seq and RNA-seq), proteomics (quantitative mass spectrometry) and chemical biology ("designer chromatin") to gain mechanistic insights into how a "mutated" histone code functions towards disrupting epigenetic landscapes that, in turn, lead to cancer progression. A world-class team of experts in cancer, chromatin and chemical biology are assembled to explore novel approaches to these devastating childhood cancers. The single goal of our Program is to illuminate the molecular mechanisms underlying "oncohistone" mutations to advance the diagnosis and exploration of therapeutic avenues for the associated pediatric cancers. Specifically, we will: i) investigate how histone mutations affect the cross-talk between other histone and DNA modifications; ii) identify the changes in chromatin landscape by histone mutations using cell-based systems, animal models and patient tumor samples; iii) characterize misregulated developmental programs that help establish tumorigenesis; and iv) specifically engineer chemically-defined chromatin templates for use in in vitro biochemical reactions aimed at a detailed mechanistic dissection of how histone mutations alter HMT activities. These studies will provide guidance for the development of therapeutic strategies designed to ameliorate the pathogenic effects of histone mutations and HMTs in these childhood cancers. Also, novel immunological reagents will be generated for much-needed immunohistochemistry (IHC) diagnosis of tumor samples.

描述（由适用提供）：全基因组测序技术允许人类癌症中表观遗传修饰剂中的体细胞突变发现前所未有的发现，提供了癌症表观遗传调节剂之间的机械联系，从而导致了新的“驱动器突变”的观点，即基于癌症表观镜镜的“驱动器突变”。在核心组蛋白中高频错义突变突变的发现，例如组蛋白H3赖氨酸27至甲基甲基（H3K27M）和甘氨酸34到精氨酸/缬氨酸（G34R/V）在儿科glioMas，H3K36M突变中，该较差的脚踏板突变是，这一点比最近有没有更好的说明。为此没有有效的疗法。我们的生化研究表明，“ K-TO-M”突变组蛋白可以抑制负责任组蛋白甲基转移酶（HMT）的酶促活性，例如H3K27甲基化的EZH2，H3K36甲基化的setD2。奇怪的是，在相同类型的癌症中永远找不到组蛋白突变和HMT突变。这些观察结果使我们假设H3'K-TO-M'突变在HMT的失活之外起着独特的功能，这可能是各个癌症的谱系特异性发病机理的关键。 Here, we propose multidisciplinary and integrated Approaches, using genetics (cell line and mouse models), epigenetics (ChIP-seq and RNA-seq), proteomics (quantitative mass spectrometry) and chemical biology ("designer chromatin") to gain mechanistic insights into how a "mutated" histone code functions towards disrupting epigenetic landscapes that, in turn, lead to cancer progression.组成了一个世界一流的癌症，染色质和化学生物学专家团队，以探索这些毁灭性童年癌症的新方法。我们程序的一个目标是阐明“酒精酮上”突变的分子机制，以推动相关儿科癌症治疗途径的诊断和探索。具体而言，我们将：i）研究组蛋白突变如何影响其他组蛋白和DNA修饰之间的串扰； ii）使用基于细胞的系统，动物模型和患者肿瘤样品来确定组蛋白突变通过组蛋白突变的变化； iii）表征有助于建立肿瘤发生的未经调节的发育计划；和iv）专门工程师化学定义的染色质模板，用于在体外生化反应，旨在详细的机械解剖，详细说明组蛋白突变如何改变HMT活性。这些研究将为制定旨在改善这些童年癌症组蛋白突变和HMT的致病作用的治疗策略提供指导。此外，将针对肿瘤样品的急需免疫组织化学（IHC）诊断生成新的免疫试剂。