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：
9142300
负责人：
CHARLES DAVID ALLIS
金额：
$ 185.51万
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/9142300
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（由申请人提供）：全基因组测序技术使得人类癌症中表观遗传修饰因子的体细胞突变得到了前所未有的发现，提供了癌症表观基因组和遗传改变之间的机制联系，表观遗传调节因子中致癌激活突变的总数导致了癌症表观遗传修饰的发生。最近关于核心组蛋白（例如组蛋白）的高频错义突变的发现最能说明这一点。儿童神经胶质瘤中的 H3 赖氨酸 27 至蛋氨酸 (H3K27M) 和甘氨酸 34 至精氨酸/缬氨酸 (G34R/V) 突变，以及儿童软骨母细胞瘤中的 H3K36M 突变，特别是对侵袭性癌症的了解仍知之甚少，并且没有有效的治疗方法。研究表明“K-to-M”突变组蛋白可以抑制相关组蛋白的酶活性甲基转移酶 (HMT)，例如用于 H3K27 甲基化的 Ezh2 和用于 H3K36 甲基化的 SETD2 奇怪的是，在同一类型的癌症中从未发现组蛋白突变和 HMT 突变。这些观察结果使我们着迷于 H3“K-to-M”。突变除了使 HMT 失活之外还发挥着不同的功能，这可能是各种癌症谱系特异性发病机制的关键。在这里，我们提出了多学科和多学科的研究。综合方法，使用遗传学（细胞系和小鼠模型）、表观遗传学（ChIP-seq 和 RNA-seq）、蛋白质组学（定量质谱）和化学生物学（“设计染色质”）来获得有关“突变”组蛋白如何发生的机制见解代码功能破坏表观遗传景观，进而导致癌症进展，由癌症、染色质和化学生物学领域的世界级专家组成的团队聚集在一起，探索解决这些问题的新方法。我们计划的唯一目标是阐明“癌组蛋白”突变的分子机制，以推进相关儿科癌症的诊断和治疗途径的探索。具体来说，我们将：i) 研究组蛋白突变如何影响交叉。 -其他组蛋白和 DNA 修饰之间的讨论；ii) 使用基于细胞的系统、动物模型和患者肿瘤样本识别组蛋白突变引起的染色质景观变化；iii) 描述有助于确定肿瘤发生的失调发育程序；设计用于体外生化反应的化学定义的染色质模板，旨在详细剖析组蛋白突变如何改变 HMT 活性，这些研究将为开发旨在改善组蛋白突变和 HMT 致病作用的治疗策略提供指导。此外，还将生产新的免疫试剂用于急需的肿瘤样本免疫组织化学（IHC）诊断。