Determining the cell of origin in Ewing sarcoma through genomic analysis

通过基因组分析确定尤文肉瘤的起源细胞

• 批准号: 10066323
• 负责人: Logan G. Spector
• 金额: $ 21.6万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-06 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066323
• 关键词: Adipocytes; Adolescent; Adolescent and Young Adult; Animal Disease Models; Biological Assay; Biology; Bone Marrow; Bone neoplasms; Cardiac Myocytes; Cells; Chromatin; Data; Data Set; Databases; Deoxyribonuclease I; Development; EWS-FLI1 fusion protein; Ewings sarcoma; FLI1 gene; Genetic Transcription; Genomics; Heterogeneity; Hypersensitivity; Link; Long QT Syndrome; Mesenchymal; Mesenchymal Stem Cells; Mesoderm; Methods; Mutation; Neural Crest; Neuroectoderm; Pediatric Neoplasm; Phenotype; Risk; Single Nucleotide Polymorphism; Site; Tumor-Derived; Undifferentiated; Variant; case control; cell transformation; cell type; cost effective; experimental study; genetic variant; genome wide association study; genome-wide; genomic variation; improved; in vivo; induced pluripotent stem cell; novel; progenitor; programs; public health relevance; relating to nervous system; statistics; success; therapy development; tumor

Abstract Ewing sarcoma (ES) is a rare but deadly bone tumor which occurs mainly in adolescents and young adults. As survival for ES has not improved beyond ~60% in the last few decades, it is critical to understand its origins in order to improve therapy. Most attempts to determine the cell of origin of ES have relied on cells transformed by the EWS-FLI1 fusion protein, which exerts a strong transcriptional program, whereas we propose a method which uses untransformed candidate cell types. We will derive induced pluripotent stem cells (iPSC) or obtain primary cells for the following cell types: Undifferentiated iPSC, iPS-mesenchymal stem cells, bone marrow- derived mesenchymal stem cells, neural crest progenitors, and neural-crest/mesenchymal stem cells. An open chromatin profile of each cell type will be obtained via the ATAC-seq assay and cross referenced with a genomewide case-control dataset on ES to nominate a cell of origin. Lastly, variants in open chromatin in the nominated cell of origin will be comprehensively characterized. The experiments outlined below represent a novel method for determining the cell of origin for ES, which if successful would point the way to more precise animal models of the disease and potentially inform the development of therapy.

摘要 尤文肉瘤（ES）是一种罕见但致命的骨肿瘤，主要发生在青少年和年轻人。作为 在过去的几十年里，ES的存活率没有提高到60%以上，因此了解其起源至关重要。 以改善治疗。大多数确定ES起源细胞的尝试都依赖于通过以下途径转化的细胞： EWS-FLI 1融合蛋白，它发挥了强大的转录程序，而我们提出了一种方法， 其使用未变换的候选细胞类型。我们将获得诱导多能干细胞（iPSC）或获得 未分化的iPSC、iPS-间充质干细胞、骨髓-骨髓间充质干细胞 衍生的间充质干细胞、神经嵴祖细胞和神经嵴/间充质干细胞。一个开放 每种细胞类型的染色质谱将通过ATAC-seq测定获得，并与 ES上的全基因组病例对照数据集来指定起源细胞。最后，在开放染色质的变异， 将全面表征指定的起源细胞。下面概述的实验代表了 一种新的方法来确定起源细胞的ES，如果成功的话， 疾病的动物模型，并可能为治疗的发展提供信息。

项目成果

CRISPR-Cas9 base editors and their current role in human therapeutics.

• DOI: 10.1016/j.jcyt.2022.11.013
• 发表时间: 2023-01
• 期刊: Cytotherapy
• 影响因子: 4.5
• 作者: Walker S. Lahr;Christopher J. Sipe;Joseph G. Skeate;Beau R. Webber;B. Moriarity