Determining the biological importance of SETBP1 functional domains to develop novel therapeutic approaches for myeloid leukemias

项目摘要/摘要 本项目旨在阐明原癌基因SETBP1(Set-bindingProtein 1)的作用机制 通过对功能结构域和细胞周期标志物的分析(目标1)，并利用这些机制数据来识别 新的治疗靶点(目标2)。阐明功能结构域在SETBP1驱动的白血病中的作用和 细胞增殖，我将突变这些结构域，并测试受干扰的构建体促进 白血病在造血祖细胞集落形成单位试验和体内的表型。我还将利用靶向基因 表达分析以了解细胞周期调节因子是如何在这些功能域的上下文中被干扰的 突变。我建议使用我们新的机制数据和初步的小分子功能筛选数据 在细胞系模型和患者样本中进行知情药物开发。我会验证未来的药物 在一种新的SETBP1突变的CNL细胞模型中进行靶点和组合，然后评估 使用世界上最大的CNL样本库之一的患者样本中最好的药物。 拟议的项目利用了我在体外和体内建模方面的专业知识，同时为我提供了 有机会发展新技能，并对翻译癌症生物学有基本的了解。常规输入 来自我的联合赞助商和OHSU的其他癌症生物学家将为我的数据和 产生创新实验的想法。Maxson博士是CNL生物学方面的领先专家， CSF3R驱动的肿瘤发生机制。她在细胞和分子生物学方面有丰富的经验。 技术和研究白血病的新致癌基因突变，使她成为指导我的理想人选 这个项目。我的共同赞助人布莱恩·德鲁克博士是一位内科科学家，也是奈特癌症中心的主任 研究所。作为一名内科科学家和靶向癌症治疗的先驱，德鲁克博士可以提供临床背景 感谢我的工作，并帮助确保我解决了与临床最相关的问题。德鲁克博士的财富 治疗开发方面的专业知识对于本提案的目标2至关重要。

PROJECT SUMMARY/ABSTRACT This project aims to elucidate the mechanism of action of the proto-oncogene SETBP1 (SET-binding protein 1) through analysis of functional domains and cell cycle markers (Aim 1), and to use this mechanistic data to identify novel therapeutic targets (Aim 2). To elucidate the role of functional domains in SETBP1-driven leukemia and cell proliferation, I will mutate these domains and test the ability of the perturbed constructs to promote the leukemic phenotype in a hematopoietic colony forming unit assay and in vivo. I will also utilize targeted gene expression analysis to understand how cell cycle regulators are perturbed in context of these functional domain mutations. I propose to use our new mechanistic data and preliminary small molecule functional screening data to conduct informed drug development in cell line models and patient samples. I will validate prospective drug targets and combinations in a novel SETBP1-mutant CNL cell line model, and then assess the efficacy of the best agents in patient samples using one of the largest repositories of CNL samples in the world. The proposed project takes advantage of my expertise in in vitro and in vivo modelling, while affording me the opportunity to develop new skills and a fundamental understanding of translational cancer biology. Regular input from my co-sponsors and other cancer biologists at OHSU will provide me with critical feedback on my data and generate ideas for innovative experiments. Dr. Maxson is a leading expert on the biology of CNL and mechanisms of CSF3R-driven oncogenesis. She has substantial experience with cellular and molecular biology techniques and investigating novel oncogenic mutations in leukemia, making her ideally suited to mentor me on this project. My co-sponsor, Dr. Brian Druker, is a physician scientist and the director of the Knight Cancer Institute. As a physician scientist and a pioneer of targeted cancer therapy, Dr. Druker can provide clinical context for my work and help to ensure that I am addressing the most clinically relevant questions. Dr. Druker’s wealth of expertise in therapeutic development is essential for Aim 2 of this proposal.