Experimental and preclinical modeling of NUP98-rearranged acute leukemia

项目概要-概述 核孔蛋白98（NUP 98）重排产生的融合癌蛋白（FO）， 伴侣基因是儿童和青少年中多种亚型的高风险骨髓恶性肿瘤的标志， 包括急性红白血病和急性巨核细胞白血病。这种白血病与不良的 结果，需要更有效的治疗。该中心的长期目标是实验和 NUP 98白血病的临床前建模是为了确定NUP 98白血病的分子作用和潜在的脆弱性， NUP 98-融合癌蛋白在白血病中的作用：人类和小鼠模型的开发和研究 系统，并开发和测试新的治疗方法。该中心已组建了一个财团， 在基因组表征、白血病建模、染色质生物学 结构生物学和临床前建模。该中心由圣裘德儿童医院的查尔斯·穆里根博士领导。 研究医院与项目共同负责人Scott Armstrong博士（Dana Farber癌症研究所）， Taosheng Chen（St Jude），Alex Daughsis（Memorial Sloan Kettering Cancer Institute），Jeffery Klco（St Jude）和 Richard Kriwacki（St Jude）.这些研究人员将共同领导四个项目， （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NUP 98融合如何驱动 利用互补的、整合的工程模型和蛋白质组学、转录组学和 表观基因组谱;（2）开发基因工程忠实的小鼠，人类和异种移植模型， NUP 98白血病的机制研究和临床前建模;（3）定义大分子 NUP 98 FOs组装的染色质和蛋白质复合物;（4）确定NUP 98中相分离的作用 （5）确定NUP 98重排白血病细胞的依赖性和脆弱性; （6）为NUP 98重排的白血病寻找更有效的治疗策略。该中心是 由一个行政核心A支持，该核心A与一个外部咨询委员会一起监督项目进展情况 互动和报告，由大卫陈博士（City of Hope）领导的基因组编辑核心B，提供专业知识 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），支持化学库筛选和药物设计与开发。这种高度 综合，互动和协同中心将提供基本的洞察机制， 不同类型NUP 98 FO的肿瘤发生，以及新的治疗方式，将在 临床前模型并转化为人体临床试验。所有数据和资源都将免费提供 通过网站、数据存储以及建立资源和基因组数据门户网站， 协会和广大科学界。

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.