Elucidating and targeting the effects of oncogenic histone mutations

项目总结/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， 已经开发了几种治疗靶向具有组蛋白突变的肿瘤的策略。组蛋白是 染色质的基本组成部分，通过以下方式调节DNA对基因表达的可及性： 组蛋白N-末端尾部的动态调节的组合翻译后修饰（PTM）。 经典的致癌组蛋白（“致癌组蛋白”）突变直接阻止了这些PTM中的一些的“书写”， 通过改变抑制分化的转录模式促进肿瘤发生。PI和他的 合作者最近描述了一个出乎意料的广泛的新癌组蛋白突变的特征， 发生在大约4%的肿瘤中。拟议工作的目标是了解其中一个子集的影响 新的癌组蛋白对染色质和肿瘤生物学的影响，并开发治疗靶向肿瘤的策略 表达癌组蛋白。该提案中提出的初步数据表明：（a）一类新的癌组蛋白 H3 N-末端精氨酸（H3 R）残基的突变改变了附近的调节性PTM， 分化，和（B）由经典H3 K36 M癌组蛋白突变驱动分化阻断可以 通过酪氨酸激酶抑制来拯救。因此，提出了实验来检验假设，H3 R 癌组蛋白突变破坏染色质景观，改变转录，并失调细胞功能， 酪氨酸激酶信号传导介导癌组蛋白诱导的分化阻断。严格测试 这些假设，实验提出（1）阐明新的癌组蛋白突变的影响， 染色质景观和染色质依赖性转录、分化和肿瘤发生，以及（2） 确定激酶信号传导的抑制如何拯救经典的癌组蛋白诱导的分化阻断。的 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 开发新的基因型定向癌症疗法。PI，纪念斯隆医学肿瘤学研究员 凯特林癌症中心（MSKCC），制定了一个5年的职业发展计划，建立在他的 化学生物学的科学背景和医学肿瘤学的临床培训。他将进行拟议的 在C博士的指导下进行研究。国际公认的癌组蛋白专家大卫阿利斯 突变和表观遗传学，并将发展染色质生物学，包括染色质相关的新技能 生物信息学和生物化学是他未来职业生涯的关键，重点是理解和 治疗靶向表观遗传驱动的癌症。这种训练，结合他的背景，导师， 以及MSKCC和合作机构洛克菲勒大学的制度环境， 成功地过渡到独立作为一个学术物理学家，科学家与他自己的实验室和赠款 经费

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.