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; 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.

项目摘要/摘要 研究：RNA结合蛋白（RBP）调节包括转录，包括转录， 基因表达的翻译和调节，并且在癌症中经常失调。通过一个 公正的遗传筛选旨在鉴定癌症特异性的RBP依赖性，我们最近确定了 恶性髓样癌症中RBM39的特定需求，并具有RNA剪接的癌症 因子突变对抗癌磺酰胺特别敏感。 RBM39是RBP RNA剪接的功能，最近，一类临床级“抗癌磺酰胺”化合物的功能 通过选择DDB1/CUL4泛素 - 岩酶复合物作为降解RBM39蛋白的降解蛋白 他们的作用机理。这是该项目的主要目标是评估差异和 正常造血与髓生效的RBM39的组织特异性需求， 并评估白血病计划和维护的RBM39要求。该提议将 利用一种新颖的有条件敲除（CKO）小鼠用于RBM39，并在 体外和体内鼠模型追求这一目标。我们希望这些投资能够进一步 了解RBM39在正常生理和癌症中的作用，并提供新的 对抗癌磺酰胺的靶向毒性和脱靶毒性的治疗见解。这些目标 特别及时的是，这些分子中的几个已经证明了出色的安全性 多个I/II期试验，现在已经成熟于最有可能的患者人群的治疗测试 RBM39降解中受益。候选人：Sydney X. Lu博士是毕业的血液学和医学 MSKCC医学系的肿瘤学研究员。他的目标是成为一个独立的任期 - 跟踪身体科学家调查血液恶性肿瘤的分子发病机理 遗传学，功能基因组学和鼠建模的结合。 Lu博士概述了五年的时间 受过指导的培训，以增强他在功能基因组学和疾病建模方面的技能。这个培训 时期将在功能性的领导者奥马尔·阿卜杜勒·瓦哈卜（Omar Abdel-Wahab）的心态下进行 造血恶性肿瘤的基因组学。 Lu博士还组建了一个由 博士。罗斯·莱文（Ross Levine），马丁·塔尔曼（Martin Tallman），迈克尔·哈拉斯（Michael Kharas）和克里斯汀·梅尔（Christine Mayr）将帮助指导他的训练 和研究。环境：MSKCC是世界上最古老，最大的私人癌症中心 超过130年的患者护理，创新研究和杰出的教育 程序。 MSKCC通过 坚定的承诺和成功支持正在寻求职业的初级教师的记录 作为独立的身体科学家。