Clinical and Genetic Origins of Monomorphic Epitheliotropic Intestinal T Cell Lymphoma

单形性上皮性肠 T 细胞淋巴瘤的临床和遗传起源

基本信息

批准号：
10566317
负责人：
Sandeep Dave
金额：
$ 41.66万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10566317
关键词：
Address Affect Biological Celiac Disease Cell Differentiation process Cell physiology Cells Clinical DNA Damage DNA Repair Development Disease Disease model Exhibits Exons Frequencies Gene Silencing Generations Genes Genetic Genetic Transcription Genomics Histone H3 Intestinal Neoplasms Intestines Knock-out Knockout Mice Knowledge Lead Lymphocyte Lymphoma Lymphomagenesis Lysine Malignant Neoplasms Measures Messenger RNA Methylation Modeling Modification Molecular Mutate Mutation Oncogene Activation Oncogenes Outcome Pathogenesis Pathway interactions Patients Phenotype Population Premalignant Cell Process Prognosis RNA Splicing Rag1 Mouse Recording of previous events Role STAT5B gene Site T-Cell Development T-Cell Lymphoma T-Lymphocyte T-cell receptor repertoire Techniques Testing Therapeutic Treatment Protocols V(D)J Recombination Work cell transformation design effective therapy genotoxicity histone methyltransferase improved innovation intraepithelial mouse model novel novel therapeutic intervention overexpression premalignant recruit response single-cell RNA sequencing standard of care tumor γδ T cells

项目摘要

ABSTRACT Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare but lethal disease with a median survival of 1 year. There is no current effective standard-of-care. Previous MEITL sequencing efforts performed by our group and others have revealed SETD2 as one of the most frequently altered genes in this disease. SETD2 directs trimethylation of the lysine 36 residue on histone H3 (H3K36me3), which in turn is associated with active transcription of genes. SETD2 has been implicated in DNA damage repair and mRNA splicing. However, the molecular role of SETD2 and its interaction with activated oncogenes in MEITL pathogenesis is largely unknown. In this proposal, we will utilize a conditional mouse model to determine how SETD2 loss contributes to the creation of a premalignant pool of intestinal intraepithelial cells (IELs), the cell of origin of MEITL. We will also investigate how the combination of SETD2 loss and activation of the oncogenes STAT5B or MYC lead to IEL transformation. Finally, we will determine the extent to which SETD2 deficiency sensitizes T lymphoma cells to a variety of genotoxic chemotherapeutics. We anticipate that the results of this work will have immediate impact on the design of effective treatment regimens that target MEITL and other SETD2-deficient lymphomas.

抽象的单态上皮型肠道T细胞淋巴瘤（MEITL）是一种罕见但致命的疾病，中位生存1年。目前没有有效的护理标准。以前的MEITL测序工作我们的小组和其他人揭示了SetD2是该疾病中最常见的基因之一。 SETD2指导组蛋白H3上赖氨酸36残基的三甲基化（H3K36me3），这又与之相关带有基因的主动转录。 SETD2与DNA损伤修复和mRNA剪接有关。但是，setD2的分子作用及其与激活的癌基因在meitl发病机理中的相互作用是在很大程度上未知。在此提案中，我们将利用条件鼠标模型来确定setD2损失如何有助于创建肠内细胞（IELS）的肠内前池，Meitl的起源细胞。我们也会研究setD2损失和Oncogenes Stat5b或Myc激活的组合如何导致IEL 转型。最后，我们将确定setD2缺乏症将T淋巴瘤细胞敏感的程度多种遗传毒性化学治疗药。我们预计这项工作的结果将立即产生影响关于靶向MEITL和其他SETD2缺陷淋巴瘤的有效治疗方案的设计。