Elucidating and targeting the effects of oncogenic histone mutations

项目摘要/摘要 组蛋白基因在癌症中经常发生突变，但大多数组蛋白突变的意义尚不清楚。 几乎没有针对含有组蛋白突变的肿瘤的治疗策略被开发出来。组蛋白是 染色质的基本成分，它通过以下方式调节DNA对基因表达的可及性 动态调节的组蛋白N末端的组合翻译后修饰(PTM)。 经典致癌组蛋白(‘oncohistone’)突变直接阻止其中一些PTM的‘写入’， 通过抑制分化的转录模式改变来促进肿瘤的发生。私家侦探和他的 合作者最近描述了一幅出人意料的广泛的新型癌组蛋白突变的图景 发生在大约4%的肿瘤中。拟议工作的目标是了解这些内容的子集的影响 核染色质与肿瘤生物学的新癌组蛋白及其靶向治疗策略的研究 表达癌组织蛋白。本提案中提出的初步数据显示：(A)一类新型癌组织蛋白 H3N端精氨酸(H3R)残基的突变改变了附近的调节PTM并损害了细胞 分化，以及(B)由经典的H3K36M癌基因突变驱动的分化阻断可以是 被酪氨酸激酶抑制挽救了。因此，提出了实验来检验H3R的假设 癌组蛋白突变扰乱染色质格局，改变转录，并扰乱细胞功能， 而酪氨酸激酶信号介导了癌组蛋白诱导的分化阻断。严格测试 这些假说、实验是为了(1)阐明新的癌组蛋白突变对肿瘤细胞的影响。 染色质景观和依赖染色质的转录、分化和肿瘤发生 确定抑制激酶信号如何挽救经典的癌组蛋白诱导的分化阻断。这个 拟议的工作将提高对癌症相关组蛋白突变的理解，并可能导致 开发新的以基因为导向的癌症疗法。纪念斯隆医学肿瘤学研究员The Pi 凯特琳癌症中心(MSKCC)在他的基础上制定了一项为期5年的职业发展计划 化学生物学的科学背景和内科肿瘤学的临床培训。他将主持拟议中的 在国际公认的癌组蛋白专家C.David Allis博士的指导下进行的研究 突变和表观遗传学，并将开发染色质生物学方面的新技术，包括与染色质相关的技术 生物信息学和生物化学，对他未来的职业生涯至关重要，专注于理解和 以表观遗传驱动的癌症为治疗靶点。这次培训，结合他的背景，导师的指导， 而MSKCC及其合作机构洛克菲勒大学的制度环境，使PI 成功地过渡到独立成为一名学术内科医生-科学家，拥有自己的实验室和 资金问题。

PROJECT SUMMARY/ABSTRACT Histone genes are frequently mutated in cancer, but the significance of most histone mutations is unknown and few strategies to therapeutically target tumors harboring histone mutations have been developed. Histones are a fundamental component of chromatin, which regulates the accessibility of DNA for gene expression through dynamically regulated combinatorial post-translational modifications (PTMs) of histones’ N-terminal tails. Classical oncogenic histone (‘oncohistone’) mutations directly prevent the ‘writing’ of some of these PTMs, promoting oncogenesis through altered transcription patterns that inhibit differentiation. The PI and his collaborators have recently characterized an unexpectedly broad landscape of novel oncohistone mutations that occur in roughly 4% of tumors. The goal of the proposed work is to understand the impact of a subset of these novel oncohistones on chromatin and tumor biology and to develop strategies to therapeutically target tumors expressing oncohistones. Preliminary data presented in this proposal show (a) that a class of novel oncohistone mutations at H3 N-terminal arginine (H3R) residues alter nearby regulatory PTMs and impair cellular differentiation, and (b) that differentiation blockade driven by the classical H3K36M oncohistone mutation can be rescued by tyrosine kinase inhibition. Therefore, experiments are proposed to test the hypotheses that H3R oncohistone mutations disrupt the chromatin landscape, alter transcription, and dysregulate cellular functions, and that tyrosine kinase signaling mediates oncohistone-induced differentiation blockade. To rigorously test these hypotheses, experiments are proposed to (1) elucidate the effects of novel oncohistone mutations on the chromatin landscape and chromatin-dependent transcription, differentiation, and tumorigenesis and (2) determine how inhibition of kinase signaling rescues classical oncohistone-induced differentiation blockade. The proposed work will improve understanding of cancer-associated histone mutations and may lead to the development of new genotype-directed cancer therapies. The PI, a Medical Oncology Fellow at Memorial Sloan Kettering Cancer Center (MSKCC), has developed a 5-year career development plan that builds upon his scientific background in chemical biology and clinical training in medical oncology. He will conduct the proposed research under the mentorship of Dr. C. David Allis, an internationally recognized expert in oncohistone mutations and epigenetics, and will develop new skills in chromatin biology including chromatin-relevant bioinformatics and biochemistry that are critical for his future career focused on understanding and therapeutically targeting epigenetically driven cancers. This training, combined with his background, mentorship, and the institutional environment of MSKCC and partner institution The Rockefeller University, positions the PI to successfully transition to independence as an academic physician-scientist with his own laboratory and grant funding.