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/文摘