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）重排向潜水员范围的融合癌蛋白（FO） 伴侣基因是儿童和青少年的高风险髓样恶性肿瘤的多种亚型的标志， 包括急性红血球血症和急性巨核细胞白血病。这种白血病与差有关 结果需要更有效的疗法。这个实验中心的长期目标和 NUP98白血病的临床前建模是确定分子作用和潜在脆弱性 通过人类和小鼠模型的开发和询问，白血病中的NUP98融合量蛋白 系统，并开发和测试新型的治疗方法。该中心已经组建了一个财团 具有基因组表征，白血病建模，染色质生物学的完整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的查尔斯·穆尔根（Charles Mullighan）博士领导 研究医院与项目共同领导者Scott Armstrong博士（Dana Farber癌症研究所）， Taosheng Chen（St Jude），Alex Kentsis（纪念Sloan Kettering Cancer Institute），Jeffery Klco（St Jude）和 理查德·克里瓦奇（Richard Kriwacki）（圣裘德）。这些研究人员将共同领导四个执行实验建模的项目 （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融合方式 使用完善，综合工程模型和蛋白质组学，转录组和的白血病发生 表观基因组谱； （2）开发一般忠实地设计的鼠标，人类和Xenographotic模型 NUP98机械询问和临床前建模的白血病； （3）定义大分子 由NUP98 FOS组装的染色质和蛋白质复合物； （4）定义相分离在NUP98中的作用 fo白血病； （5）定义NUP98重新培养白血病的依赖性和脆弱性； （6）为NUP98重新培养的白血病制定更有效的治疗策略。中心是 由行政核心A支持，具有外部顾问委员会将监督项目进度 互动和报告，由David Chen（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基因组编辑扫描和屏幕；和由Zoran博士领导的化学核心C 支持化学库筛选以及药物设计和开发的Rankovic（St Jude）。这很高 综合，互动和协同中心将提供对机制机制的基本见解 NUP98 FO的不同类别的肿瘤以及将在 临床前模型，转化为人类临床试验。所有数据和资源将免费提供 通过网站，数据沉积以及将资源和基因组数据门户网站建立到Fusonc2 财团和广泛的科学界。