Project 1: Decoding Origin and Modeling Oncohistones in Pediatric Cancers

项目总结 我们和其他人最近在相当一部分儿童和年轻人中发现了组蛋白3变体的突变 患有致命脑瘤和致残骨癌的成年人。这是癌症中一个非常新的未知领域 将受益于对疾病生物学的更好理解和准确实验模型的设计 重述这些表观遗传性癌症，正如我们在这个项目中的目标一样。令人惊讶的是，我们进一步获得的数据 其他研究表明，我们所说的这些“癌组织蛋白”可能出现在特定的 器官发育正常。事实上，给定H3亚型中的每个突变都有年龄、器官和解剖位置 在一个器官内，特定的。在HGA中增加了复杂性，因为我们显示了不同的添加要求 遗传改变也是年龄、大脑位置和H3变异所特有的。肿瘤组蛋白是一个新的专业 癌症领域的范式转变，关于它们如何在肿瘤形成中发挥作用的知识有限。我们的 该项目与本计划中的其他项目相结合，旨在克服这一重大知识差距，并 有效治疗的障碍。我们的目标是“破译”这些突变如何机械地影响表观基因组。 发展背景下的肿瘤景观(目标1和2)。我们将提供急需的相关信息 组蛋白突变的实验模型(目标2)，并在HGA中蓬勃发展以忠实地概括人类疾病 (目标2和3)。我们的团队(Jabado/Majewski)是首次在人类中发现组蛋白突变的两个小组之一 疾病。我们有关于HGA和其他儿科癌症的第一手知识，以及无与伦比的肿瘤获取途径 样本、动物模型和临床信息。Allis发现了H3.3，Allis和Muir实验室是 生物化学和机械方面的最佳定位有助于研究这些突变。这是自然的协同效应， 本计划中的三个项目之间的交叉互动和资源和材料共享。我们会 获得必要的支持，以集成和分析我们在原发肿瘤和 模型系统同时受益于资源和新颖的技术方法，并与复杂的 基因组学/表观基因组学测序核心使用的数据集(Majewski和表观基因组专家共同 调查员Pastinen)。定量蛋白质组学核心(Garcia)，为数不多的能够研究的小组之一 组蛋白突变在蛋白质水平上的组合将使组蛋白突变的精确测量成为可能 病人和小鼠样本以及我们的实验模型。这其中的自然互动和协同效应 该计划及其内部的专业水平确保了我们将在这些癌症方面取得重大突破 这可以转化为改善对患者的护理。

PROJECT SUMMARY We and others recently identified mutations in histone 3 variants in a significant fraction of children and young adults with a deadly brain tumor and maiming bone cancers. This is a very new uncharted area in cancer that will benefit from improved understanding of disease biology and the design of accurate experimental models to recapitulate these epigenetic cancers as we aim to do in this project. Strikingly data we further acquired with other funding suggest these “oncohistones” as we labeled them possibly arise during specific windows of normal organ development. Indeed, each mutation in a given H3 isoform has age, organ and anatomic location within an organ, specificities. There is added complexity in HGA as we showed requirement of distinct added genetic alterations that are also age, brain location and H3 variant specific. Oncohistones are a new major paradigm shift in the field of cancer, and limited knowledge exists on how they act in tumor formation. Our project, integrated with other projects in this Program, aims to overcome this major knowledge gap and obstacle to effective therapy. We aim to “decode” how these mutations mechanistically affect the epigenomic landscape in tumors in the context of Development (Aims 1 and 2). We will provide critically needed relevant experimental models of histone mutations (Aim 2) and thrive to faithfully recapitulate human disease in HGA (Aims 2 and 3). Our group (Jabado/Majewski) was one of two to first identify a histone mutation in human disease. We have first-hand knowledge on HGA and other pediatric cancers and unparalleled access to tumor samples, animal models and clinical information. Allis identified H3.3 and the Allis and Muir labs are one of the best positioned to biochemically and mechanistically help study these mutations. There is natural synergy, cross-interactions and sharing of resources and materials between the three projects in this Program. We will receive essential support to integrate and analyse the vast datasets we are generating in primary tumors and model systems while benefiting from the resources and novel technical approaches and integration of complex datasets used by the Genomics/Epigenomics Sequencing core (Majewski and the epigenomic expert co- investigator Pastinen). The Quantitative proteomics core (Garcia), one of the rare groups able to study combination of mutations in histones on the protein level will allow precise measurement of histone mutants in patients and mouse samples and our experimental models. The natural interactions and synergies within this program and the level of expertise within it ensure that we will make significant breakthroughs in these cancers that can translate into improved care for patients.