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

确定 SETBP1 功能域的生物学重要性，以开发新的髓系白血病治疗方法

• 批准号: 9759641
• 负责人: Sarah Ann Carratt
• 金额: $ 6.12万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759641
• 关键词: AT-Hook Motifs; Address; Age; Binding; Binding Proteins; Biological; Biology; Bone Marrow; Bone Marrow Transplantation; CSF3R gene; Cancer Biology; Cell Cycle; Cell Cycle Progression; Cell Cycle Proteins; Cell Cycle Regulation; Cell Line; Cell Proliferation; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Clinical; Colony-Forming Units Assay; Complex; DNA Binding; DNA Binding Domain; Data; Development; Disease; Disease model; Drug Combinations; Drug Screening; Drug Targeting; Ensure; Feedback; Future; Gene Expression; Gene Expression Profiling; Granulocyte Colony-Stimulating Factor Receptors; Growth; Hematopoietic; In Vitro; Institutes; Juvenile Myelomonocytic Leukemia; Leukemic Cell; Malignant Neoplasms; Mediating; Medical Genetics; Mentors; Mentorship; Modeling; Molecular; Molecular Biology Techniques; Molecular and Cellular Biology; Mus; Mutate; Mutation; Myeloid Leukemia; Myeloproliferative disease; Names; Oncogenes; Oncogenic; Patients; Phenotype; Physicians; Positioning Attribute; Production; Protein Phosphatase 2A Regulatory Subunit PR53; Proto-Oncogenes; Protocols documentation; Regulation; Role; Sampling; Scientist; Sequence Homology; Signal Transduction; Small Interfering RNA; Testing; Therapeutic; Transcriptional Regulation; Tumor Suppressor Proteins; Work; base; clinical phenotype; clinically relevant; drug development; experience; experimental study; hematopoietic gene; high throughput screening; improved; in vivo; in vivo Model; innovation; insight; knock-down; leukemia; mutant; neutrophil; new therapeutic target; novel; novel therapeutic intervention; outcome forecast; overexpression; programs; promoter; prospective; protein expression; repository; screening; skills; small molecule; targeted cancer therapy; targeted treatment; therapeutic development; therapy development; tumor; tumorigenesis

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.

项目总结/摘要 本项目旨在阐明原癌基因SETBP 1（SET结合蛋白1）的作用机制。 通过分析功能结构域和细胞周期标志物（目的1），并使用此机制数据来识别 新的治疗靶点（目标2）。为了阐明功能结构域在SETBP 1驱动的白血病中的作用， 细胞增殖，我将突变这些结构域，并测试扰动的构建体促进细胞增殖的能力。 造血集落形成单位测定和体内白血病表型。我还将利用靶向基因 表达分析，以了解细胞周期调节因子如何在这些功能域的背景下受到干扰 突变。我建议使用我们新的机理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的药物开发。我将验证预期药物 在新的SETBP 1-突变CNL细胞系模型中的靶点和组合，然后评估靶点和组合的功效。 使用世界上最大的CNL样本库之一， 该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 有机会发展新的技能和对转化癌症生物学的基本理解。常规输入 来自我的共同赞助者和OHSU的其他癌症生物学家将为我提供关于我的数据的关键反馈， 为创新实验提供思路。Maxson博士是CNL生物学方面的领先专家， CSF 3 R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 技术和研究白血病中的新致癌突变，使她非常适合指导我 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，也是骑士癌症中心的主任。 院作为一名医生科学家和靶向癌症治疗的先驱，Druker博士可以提供临床背景 我的工作和帮助，以确保我解决最临床相关的问题。德鲁克博士的财富 在治疗开发的专业知识是必不可少的目标2，这一建议。