Dissecting the Roles and Requirements for RBM39 in Acute Myeloid Leukemia and Normal Hematopoiesis

剖析 RBM39 在急性髓系白血病和正常造血中的作用和要求

• 批准号: 10615499
• 负责人: Sydney X Lu
• 金额: $ 24.16万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615499
• 关键词: Acute Myelocytic Leukemia; Address; Advisory Committees; Biological Assay; Blood; CRISPR screen; Cancer Center; Cell physiology; Cells; Clinical; Complex; Custom; Data; Dependence; Development; Disease model; Environment; Evaluation; Faculty; Gene Expression; Gene Expression Regulation; Gene Mutation; Genetic; Genetic Screening; Genetic Transcription; Goals; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Immunology; In Vitro; Individual; Intelligence; Investigation; Knockout Mice; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Medical Oncology; Medicine; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Modeling; Molecular; Mus; Mutation; Myelogenous; Myeloproliferative disease; Pathogenesis; Patient Care; Pharmaceutical Preparations; Pharmacology; Phase I/II Trial; Physicians; Physiology; Play; Privatization; Production; Proteins; RNA Binding; RNA Processing; RNA Recognition Motif; RNA Splicing; RNA-Binding Proteins; Research; Role; Safety; Scientist; Somatic Mutation; Spliced Genes; Sulfonamides; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Training; Translations; Ubiquitin; Work; acute myeloid leukemia cell; anti-cancer; cancer cell; cancer type; career; cell type; conditional knockout; experience; experimental study; functional genomics; in vivo; innovation; insight; leukemia; leukemia initiating cell; member; mouse model; novel; novel therapeutics; patient derived xenograft model; patient population; progenitor; programs; protein function; side effect; skills; tenure track; therapeutic evaluation; ubiquitin ligase

PROJECT SUMMARY/ABSTRACT Research: RNA binding proteins (RBPs) regulate diverse cellular processes including transcription, translation, and regulation of gene expression, and are frequently dysregulated in cancers. Through an unbiased genetic screen aimed at identifying cancer-specific RBP dependencies, we recently identified a specific requirement for RBM39 in malignant myeloid cancers and that cancers bearing RNA splicing factor mutations as being particularly sensitive to the anti-cancer sulfonamides. RBM39 is an RBP that functions in RNA splicing and recently, a class of clinical-grade “anti-cancer sulfonamide” compounds were demonstrated to degrade RBM39 protein by co-opting the Ddb1/CUL4 ubiquitin-ligase complex as their mechanism of action. Thus, the primary goal of this project is to assess differential and tissue-specific requirements for RBM39 in normal hematopoiesis versus myeloid malignancies, and to assess requirements for RBM39 for leukemia initiation and maintenance. This proposal will utilize a novel conditional knockout (cKO) mouse for Rbm39 and several associated newly developed in vitro and in vivo murine models to pursue this goal. We expect these investigations to further our understanding of the role of RBM39 in normal physiology and cancer as well as provide new therapeutic insights into the on- and off-target toxicities of the anti-cancer sulfonamides. These goals are particularly timely given that several of these molecules have already proven excellent safety in multiple phase I/II trials and are now ripe for therapeutic testing in a patient population most likely to benefit from RBM39 degradation. Candidate: Dr. Sydney X. Lu is a graduating hematology & medical oncology fellow in the Department of Medicine at MSKCC. He aims to become an independent, tenure- track physician-scientist investigating the molecular pathogenesis of hematological malignancies through a combination of genetics, functional genomics, and murine modeling. Dr.Lu has outlined a five-year period of mentored training to strengthen his skills in functional genomics and disease modeling. This training period will be carried out under the mentorship of Dr. Omar Abdel-Wahab, a leader in the functional genomics of hematopoietic malignancies. Dr. Lu has also assembled an advisory committee composed of Drs. Ross Levine, Martin Tallman, Michael Kharas, and Christine Mayr who will help guide his training and research. Environment: MSKCC is the world's oldest and largest private cancer center, devoting more than 130 years to exceptional patient care, innovative research, and outstanding educational programs. MSKCC exposes trainees to an exceptionally robust academic research environment with a strong commitment and track record of successfully supporting junior faculty who are seeking careers as independent physician-scientists.

项目概要/摘要 研究：RNA 结合蛋白 (RBP) 调节多种细胞过程，包括转录、 翻译和基因表达的调节，并且在癌症中经常失调。 我们最近发现，旨在识别癌症特异性 RBP 依赖性的无偏见基因筛查 恶性骨髓癌和带有 RNA 剪接的癌症对 RBM39 的特殊要求 因子突变对抗癌磺胺类药物特别敏感，RBM39 是一种 RBP。 RNA剪接中的功能以及最近出现的一类临床级“抗癌磺酰胺”化合物 旨在证明通过选择 Ddb1/CUL4 泛素连接酶复合物来降解 RBM39 蛋白 因此，该项目的主要目标是评估差异和作用。 正常造血与骨髓恶性肿瘤中 RBM39 的组织特异性要求， 并评估 RBM39 对白血病起始和维持的要求。 利用 Rbm39 的新型条件敲除 (cKO) 小鼠和一些新开发的相关产品 我们期望这些研究能够进一步推动我们的体外和体内小鼠模型。 了解 RBM39 在正常生理和癌症中的作用，并提供新的 对抗癌磺胺类药物的靶向和脱靶毒性的治疗见解。 鉴于其中一些分子已被证明具有出色的安全性，因此特别及时 多项 I/II 期试验，现在已经成熟，可以在最有可能出现这种情况的患者群体中进行治疗测试 受益于 RBM39 降解 候选人：Sydney X. Lu 博士是一名血液学和医学专业毕业生。 他是 MSKCC 医学系的肿瘤学研究员，目标是成为一名独立的终身教授。 跟踪医师科学家研究血液恶性肿瘤的分子发病机制 卢博士结合遗传学、功能基因组学和小鼠模型，概述了一个五年期。 指导培训，以加强他在功能基因组学和疾病建模方面的技能。 期间将在 Omar Abdel-Wahab 博士的指导下进行，他是职能领域的领导者 陆博士还组建了一个造血系统恶性肿瘤基因组学咨询委员会。 Ross Levine、Martin Tallman、Michael Kharas 和 Christine Mayr 博士将帮助指导他的训练 和研究环境：MSKCC 是世界上历史最悠久、规模最大的私立癌症中心，致力于 130 多年来致力于卓越的患者护理、创新的研究和出色的教育 MSKCC 为学员提供了一个异常强大的学术研究环境。 坚定的承诺和成功支持正在寻求职业的初级教师的记录 作为独立的医师科学家。