Experimental and preclinical modeling of NUP98-rearranged acute leukemia

NUP98重排急性白血病的实验和临床前模型

• 批准号: 10230523
• 负责人: Charles G. Mullighan
• 金额: $ 17.95万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230523
• 关键词: Acute; Acute Erythroblastic Leukemia; Acute Megakaryocytic Leukemias; Acute leukemia; Address; Adolescent; Biological Models; Biology; CRISPR/Cas technology; Cancer Biology; Chemicals; Chemistry; Child; Childhood Leukemia; Chimeric Proteins; Chromatin; Cities; Clinical Trials; Communities; Congresses; Core Facility; Dana-Farber Cancer Institute; Dependence; Development; Drug Design; Engineering; Erythroid; Experimental Models; FLT3 gene; Fusion Oncogene Proteins; Genes; Genomics; Goals; HOXA9 gene; Homeobox; Human; In Vitro; Institutes; Lead; Leukemic Cell; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Modality; Modeling; Molecular; Morphology; Mus; Mutation; Myeloproliferative disease; Nuclear Pore Complex Proteins; Outcome; Phase; Pre-Clinical Model; Proteins; Proteomics; RB1 gene; Reporting; Research Personnel; Resources; Role; Saint Jude Children' s Research Hospital; Scanning; Structure; Testing; Therapeutic; Transcriptional Regulation; Translating; Treatment Efficacy; Validation; WT1 gene; Xenograft Model; Zoran; base; chromatin protein; clinical phenotype; data portal; data resource; data submission; drug development; drug discovery; effective therapy; epigenomics; genome editing; genomic data; high risk; human model; improved outcome; in vivo; insight; leukemia; leukemogenesis; mouse model; novel therapeutic intervention; novel therapeutics; protein complex; response; small molecule inhibitor; small molecule libraries; structural biology; transcriptomics; tumorigenesis; web site

PROJECT SUMMARY - Overview Fusion oncoproteins (FO) arising from the rearrangement of Nucleoporin 98 (NUP98) to a diverse range of partner genes are a hallmark of multiple subtypes of high risk myeloid malignancies in children and adolescents, including acute erythroleukemia and acute megakaryoblastic leukemia. Such leukemias are associated with poor outcome, and more effective therapies are required. The long-term goal of this Center for Experimental and Preclinical Modeling of NUP98 Leukemia is to determine the molecular role, and potential vulnerabilities, of NUP98-fusion oncoproteins in leukemia through the development and interrogation of human and mouse model systems, and to develop and test novel therapeutic approaches. The Center has assembled a consortium of investigators with complementary expertise in genomic characterization, leukemia modeling, chromatin biology, structural biology and preclinical modeling. The Center is led by Dr Charles Mullighan of St Jude Children’s Research Hospital together with Project Co-Leaders Drs Scott Armstrong (Dana Farber Cancer Institute), Taosheng Chen (St Jude), Alex Kentsis (Memorial Sloan Kettering Cancer Institute), Jeffery Klco (St Jude) and Richard Kriwacki (St Jude). These investigators will co-Lead four projects performing experimental modeling (Project 1), investigating chromatin biology (Project 2), phase separation (Project 3) and drug development (Project 4) that will address the following questions and unmet needs: (1) to define how NUP98 fusions drive leukemogenesis using complementary, integrative engineered models and proteomic, transcriptomic and epigenomic profiles; (2) to develop genetically faithful engineered mouse, human and xenograft models of NUP98 leukemia for mechanistic interrogation and preclinical modeling; (3) to define the macromolecular chromatin and protein complexes assembled by NUP98 FOs; (4) to define the role of phase separation in NUP98 FO leukemogenesis; (5) to define the dependencies and vulnerabilities of NUP98-rearranged leukemic cells; and (6) to develop more effective therapeutic strategies for NUP98-rearranged leukemia. The Center is supported by an Administrative Core A that with an External Advisory Board will oversee project progress interaction and reporting, a Genome Editing Core B led by Dr David Chen (City of Hope) that provides expertise and support for CRISPR/Cas9 genome editing scans and screens; and a Chemistry Core C led by Dr Zoran Rankovic (St Jude) that supports chemical library screen and drug design and development. This highly integrated, interactive and synergistic Center will provide fundamental insights into the mechanisms of oncogenesis of the different classes of NUP98 FO, and new therapeutic modalities that will be validated in preclinical models and translated into human clinical trials. All data and resources will be made freely available by websites, data deposition, and establishment of resource and genomic data portals to the FusOnC2 consortium and broad scientific community.

项目摘要 - 概述 由核孔蛋白 98 (NUP98) 重排至多种不同的融合癌蛋白 (FO) 伴侣基因是儿童和青少年高风险骨髓恶性肿瘤多种亚型的标志， 包括急性红白血病和急性巨核细胞白血病。此类白血病与贫困有关 的结果，并且需要更有效的治疗方法。本实验中心的长远目标 NUP98 白血病的临床前建模旨在确定 NUP98 白血病的分子作用和潜在的脆弱性 通过人类和小鼠模型的开发和研究研究白血病中的 NUP98 融合癌蛋白 系统，并开发和测试新的治疗方法。该中心组建了一个联盟 在基因组表征、白血病建模、染色质生物学等方面具有互补专业知识的研究人员， 结构生物学和临床前建模。该中心由圣裘德儿童医院的 Charles Mullighan 博士领导 研究医院与项目联合领导者 Scott Armstrong 博士（达纳法伯癌症研究所）一起， 陈涛生 (St Jude)、Alex Kentsis (纪念斯隆·凯特琳癌症研究所)、Jeffery Klco (St Jude) 和 理查德·克里瓦奇（圣裘德）。这些研究人员将共同领导四个项目进行实验建模 （项目1），研究染色质生物学（项目2），相分离（项目3）和药物开发 （项目 4）将解决以下问题和未满足的需求：（1）定义 NUP98 融合如何驱动 使用互补、综合工程模型和蛋白质组学、转录组学和 表观基因组概况； (2) 开发基因忠实的工程小鼠、人类和异种移植模型 用于机制询问和临床前建模的 NUP98 白血病； (3)大分子的定义 由 NUP98 FO 组装的染色质和蛋白质复合物； (4) 定义NUP98中相分离的作用 FO 白血病发生； (5) 明确NUP98重排白血病细胞的依赖性和脆弱性； (6)针对NUP98重排白血病开发更有效的治疗策略。该中心是 由行政核心 A 提供支持，并由外部顾问委员会监督项目进展 互动和报告，由 David Chen 博士（希望之城）领导的基因组编辑核心 B，提供专业知识 并支持 CRISPR/Cas9 基因组编辑扫描和筛选；以及由 Zoran 博士领导的化学核心 C Rankovic（St Jude）支持化学库筛选以及药物设计和开发。这高度 综合、互动和协同中心将提供对机制的基本见解 不同类别 NUP98 FO 的肿瘤发生，以及将在 临床前模型并转化为人体临床试验。所有数据和资源将免费提供 通过网站、数据沉积以及建立 FusOnC2 的资源和基因组数据门户 财团和广泛的科学界。