Replication stress in hematopoiesis and lymphomagenesis

造血和淋巴瘤发生中的复制应激

基本信息

批准号：
10057366
负责人：
CHRISTINE M. EISCHEN
金额：
$ 42.8万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057366
关键词：
Acute Apoptosis B-Cell Lymphomas B-Lymphocytes Biochemical Biological Biology Blood Cells Bone Marrow CD34 gene Cells Cellular Stress Cessation of life Chronic Critical Pathways DNA DNA Damage DNA Repair DNA biosynthesis DNA replication fork Data Defect Development Genes Genetic Genome Genome Stability Genomic Instability Growth Heat shock proteins Hematologic Neoplasms Hematology Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Human Immunologic Deficiency Syndromes In Vitro Knockout Mice Lead Link Lymphoma Lymphoma cell Lymphomagenesis MYC gene Malignant Neoplasms Mediating Methods Mus Myelogenous Oncogenes Pancytopenia Pathology Pathway interactions Physiological Predisposition Process Proteins Radiation Reporting Resolution Role Single-Stranded DNA Stimulus Stress T-Cell Development T-Cell Lymphoma T-Lymphocyte Techniques Testing Therapeutic Intervention Time biological adaptation to stress exhaustion genetic approach genome integrity genome-wide improved in vivo in vivo evaluation innovation insight loss of function mouse model replication stress self-renewal stem cells tumor tumorigenesis

项目摘要

Summary The hematopoietic system is particularly sensitive to stimuli that cause DNA replication stress, which can result in DNA breaks. Defects in the ability to properly respond to this stress are linked to a predisposition to hematologic malignancies, hematopoietic cell deficiencies, and bone marrow failure. Recent advances include the identification of genes that respond to DNA replication stress and a greater understanding of genes necessary for hematopoiesis of specific lineages, but much remains unknown about both processes and how they intersect to cause pathology. Moreover, DNA replication stress is observed in human cancers, is induced by oncogenes such as Myc, causes DNA damage, and contributes to genome instability, but it remains poorly understood. Smarcal1 and more recently, Zranb3 were identified and evaluated biochemically and by in vitro studies to localize to replication forks and be critical for responding to DNA replication stress. Smarcal1 and Zranb3 are fork remodelers and reverse replication forks to allow repair of damaged DNA and rewind single-stranded DNA. Both Smarcal1 and Zranb3 have similar functions, but biochemical differences are reported. However, the functions of Zranb3 and Smarcal1 and whether they are redundant or complementary at times of replication stress or have unique functions in vivo has not been explored. Recently, we genetically demonstrated that Smarcal1 was essential for mediating the effects of acute DNA replication stress on hematopoietic stem and progenitor cells and contributed to the development of T cell lymphoma. Our preliminary data support the hypothesis that Zranb3 contributes to hematopoiesis and lymphomagenesis in ways distinct from Smarcal1, and that Zranb3 and Smarcal1 together contribute to hematopoiesis and lymphoma development. Therefore, we propose three Aims with in vivo genetic approaches to test this hypothesis. 1) Investigate the role of Zranb3 in Myc-induced replication stress and its contribution to acute and chronic replication stress-induced lymphoma development. 2) Determine the role of Zranb3 in hematopoiesis and hematopoietic stem and progenitor cell replication stress. 3) Evaluate the combined loss of function of Zranb3 and Smarcal1 in hematopoiesis and lymphomagenesis. Innovative concepts are tested with a new mouse model and multiple approaches, including high-resolution genome wide end-sequencing. Completion of these Aims will significantly advance understanding into DNA replication stress proteins and their contribution to genome stability, hematopoiesis, and hematological malignancies.

概括造血系统对引起 DNA 复制应激的刺激特别敏感，这可能会导致 DNA 断裂。正确应对这种压力的能力缺陷是与血液系统恶性肿瘤、造血细胞缺陷的易感性有关，骨髓衰竭。最近的进展包括识别对 DNA 做出反应的基因复制压力和对特定造血所需基因的更深入了解谱系，但对于这两个过程以及它们如何交叉导致病理。此外，在人类癌症中观察到 DNA 复制应激，该应激是由 Myc 等癌基因会导致 DNA 损伤，并导致基因组不稳定，但它仍然知之甚少。 Smarcal1 和最近的 Zranb3 被识别和评估通过生物化学和体外研究定位到复制叉并对响应至关重要 DNA复制压力。 Smarcal1 和 Zranb3 是分叉重塑器和反向复制叉子可以修复受损的 DNA 并倒带单链 DNA。 Smarcal1 和 Zranb3 具有相似的功能，但据报道存在生化差异。然而，功能 Zranb3 和 Smarcal1 的关系以及它们在复制应激或在体内具有独特的功能尚未被探索。最近，我们基因证明 Smarcal1 对于介导急性 DNA 的影响至关重要造血干细胞和祖细胞的复制应激，并导致 T细胞淋巴瘤的发展。我们的初步数据支持 Zranb3 的假设以与 Smarcal1 不同的方式促进造血和淋巴瘤发生，并且 Zranb3 和 Smarcal1 共同促进造血和淋巴瘤的发展。因此，我们提出了体内遗传方法的三个目标来检验这一假设。 1）研究 Zranb3 在 Myc 诱导的复制应激中的作用及其对急性和慢性复制应激的贡献慢性复制应激诱导淋巴瘤的发展。 2) 确定Zranb3在其中的作用造血和造血干细胞和祖细胞复制应激。 3）评估 Zranb3 和 Smarcal1 在造血和淋巴瘤发生中的功能联合丧失。使用新的小鼠模型和多种方法测试创新概念，包括高分辨率全基因组末端测序。这些目标的完成将显着加深对 DNA 复制应激蛋白及其对基因组贡献的了解稳定性、造血和血液恶性肿瘤。