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.

项目总结/摘要 研究：RNA结合蛋白（RBP）调节多种细胞过程，包括转录， 翻译和基因表达调控，并且在癌症中经常失调。通过 无偏见的遗传筛选，旨在确定癌症特异性RBP的依赖性，我们最近发现， 恶性骨髓癌对RBM 39的特异性需求， 因子突变对抗癌磺胺类药物特别敏感。RBM 39是一种RBP， 最近，一类临床级的“抗癌磺酰胺”化合物 通过选择Ddb 1/CUL 4泛素连接酶复合物， 他们的行动机制。因此，该项目的主要目标是评估差异和 正常造血与骨髓恶性肿瘤中对RBM 39的组织特异性需求， 并评估白血病起始和维持对RBM 39的需求。这项建议会 利用一种新的条件性敲除（cKO）小鼠的Rbm 39和几个相关的新开发的， 体外和体内小鼠模型来实现这一目标。我们希望这些调查能进一步促进我们的 了解RBM 39在正常生理学和癌症中的作用，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。这些目标 特别及时，因为这些分子中的几种已经被证明具有极好的安全性， 多个I/II期试验，现在已经成熟，可以在最有可能 从RBM 39降解中受益。候选人：悉尼X博士。卢是一名即将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，终身教职- 跟踪医生科学家调查血液恶性肿瘤的分子发病机制， 遗传学、功能基因组学和鼠模型的组合。卢博士概述了一个五年期 他接受了一系列指导培训，以加强他在功能基因组学和疾病建模方面的技能。本次培训 期间将在奥马尔·阿卜杜勒-瓦哈卜博士的指导下进行，奥马尔·阿卜杜勒-瓦哈卜博士是职能部门的领导人。 造血系统恶性肿瘤的基因组学卢博士还组建了一个咨询委员会， Drs.罗斯·莱文、马丁·塔尔曼、迈克尔·卡拉斯和克莉丝汀·迈尔将帮助指导他的训练 与研究环境：MSKCC是世界上最古老，最大的私人癌症中心，致力于 130多年来，卓越的病人护理，创新的研究，和杰出的教育 程序. MSKCC为学员提供了一个非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生涯的初级教师的记录 作为独立的医学科学家。