Investigating the role of KLF5 genomic alterations in tumorigenesis

项目总结 张晓阳博士是戴纳大学马修·迈耶森博士实验室的博士后研究员。 法伯癌症研究所和布罗德研究所。他的长期职业目标，与 NCI，是通过确定癌症发展的机制来减少癌症相关的死亡率和痛苦 并确定有吸引力的治疗靶点。为了实现这一目标，张博士独特地利用了这两种手段 基因组学以及细胞和分子生物学方法来回答与癌症有关的基本问题 生物学。 对人类癌症的大规模基因组调查最近发现了两种类型的基因组改变 KLF5基因。张博士发现了一个非编码区，位于KLF5基因附近，充满了超 增强剂，在几种癌症类型中被局部扩增，这种扩增与KLF5过度相关。 表情。此外，迈耶森博士的实验室在DNA结合中发现了显著的热点突变 KLF5基因在非小细胞肺癌中的结构域所有这些都强烈地表明，KLF5是一部小说 致癌基因。这项提议旨在描述这些基因组改变在调节KLF5活性中的作用 并促进肿瘤的发生。目标1将研究超级增强子扩增与KLF5之间的联系 以及KLF5在不同癌症类型中过度表达的致癌后果。然后, 目的研究KLF5热点突变的致癌功能。 基因组编辑工具产生的突变细胞系。最后，在AIM 3中，CRISPR介导的启动子/增强子 将开展筛选以确定KLF5突变体及其相关靶点的功能结合位点 基因和途径。这项拟议的研究将提高我们对致癌基因转录如何 促进癌症发展的因素可能会产生新的治疗靶点。 张博士将在生物统计学、计算生物学和基因组编辑方面接受更多的研究培训，以及 同时，通过赠款编写和领导力方面的培训，促进其职业发展。这个 张博士可获得的优秀研究环境和设施包括实验室空间和完整的 达纳-法伯癌症研究所和布罗德研究所的机构准入。在K99阶段，Dr。 张的研究和培训将在马修·迈耶森博士的主要指导下进行，马修·迈耶森博士是 癌症基因组学领域的领先者，并将通过与计算专家的合作而得到进一步加强 生物学和高通量基因筛查，以及由以下咨询委员会提供的指导 迈尔斯·布朗博士、布拉德利·伯恩斯坦博士、张峰博士和列维·加拉韦博士。

PROJECT SUMMARY Dr. Xiaoyang Zhang is a postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at Dana- Farber Cancer Institute and the Broad Institute. His long-term career goal, in alignment with the mission of the NCI, is to reduce cancer-associated mortality and suffering by determining mechanisms of cancer development and identifying attractive therapeutic targets. To accomplish this goal, Dr. Zhang uniquely leverages both genomics and cellular and molecular biology methods to answer fundamental questions relating to cancer biology. Large-scale genomic surveys of human cancer have recently found two types of genomic alterations of the KLF5 gene. Dr. Zhang identified that a non-coding region, nearby the KLF5 gene and filled with super- enhancers, is focally amplified in several cancer types and the amplification correlates with KLF5 over- expression. In addition, Dr. Meyerson's laboratory identified significant hot-spot mutations in the DNA binding domain of the KLF5 gene in non-small cell lung cancers. All these strongly suggest that KLF5 is a novel oncogene. This proposal aims to characterize the role of these genomic alterations in regulating KLF5 activity and promoting tumorigenesis. Aim 1 will study the link between the super-enhancer amplification and KLF5 over-expression, and the oncogenic consequences of KLF5 over-expression in diverse cancer types. Then, Aim 2 will study the oncogenic function of KLF5 hot-spot mutations by using isogenic KLF5 wild-type and mutant cell lines generated by genome-editing tools. Finally, in Aim 3, a CRISPR-mediated promoter/enhancer screening will be developed to identify the functional binding sites of KLF5 mutants and their associated target genes and pathways. The proposed research will improve our understanding of how oncogenic transcription factors promote cancer development and may yield novel therapeutic targets. Dr. Zhang will gain more research training in biostatistics, computational biology and genome-editing, and simultaneously enhance his career development through training in grant-writing and leadership. The outstanding research environment and facilities available to Dr. Zhang include laboratory space and full institutional access at both Dana-Farber Cancer Institute and the Broad Institute. During the K99 phase, Dr. Zhang's research and training will be carried out under the primary mentorship of Dr. Matthew Meyerson, a leader in cancer genomics, and will be additionally enhanced by collaborations with experts in computational biology and high-throughput genetic screening, as well as by mentoring from an advisory committee consisting of Drs. Myles Brown, Bradley Bernstein, Feng Zhang, and Levi Garraway.