Metabolic Network Remodeling in Epstein-Barr Virus Lymphomagenesis

EB 病毒淋巴瘤发生中的代谢网络重塑

• 批准号: 9899193
• 负责人: Benjamin Elison Gewurz
• 金额: $ 44.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899193
• 关键词: Adult; African Burkitt' s lymphoma; Aging; Architecture; B-Lymphocytes; Biochemical Pathway; Burkitt Lymphoma; CRISPR screen; Cancerous; Carbon; Cell Cycle; Cell Size; Cell division; Cells; Central Nervous System Lymphoma; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Dependence; Disease; Drug Metabolic Detoxication; Elderly; Embryo; Enzymes; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Epstein-Barr Virus-Related Malignant Neoplasm; Epstein-Barr pathogenesis; Folic Acid Antagonists; Glycine; Goals; Growth; HIV; Hodgkin Disease; Homebound Persons; Hour; Human; Human Herpesvirus 4; Immune; Immune system; Immunocompromised Host; Infection; LMP1; Lead; Lipid Peroxides; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitosis; Modeling; NADP; Nasopharynx Carcinoma; Oncogenes; Oncogenic Viruses; Oncoproteins; Organ Transplantation; Oxidation-Reduction; Pathway interactions; Patients; Phase; Prevention strategy; Production; Proteomics; Purines; Reaction; Reactive Oxygen Species; Regimen; Rest; Role; Serine; Testing; Therapeutic; Tissues; acquired immunodeficiency; age related; cell growth; cell transformation; co-infection; congenital immunodeficiency; genome-wide; large cell Diffuse non-Hodgkin' s lymphoma; lipid biosynthesis; lymphoblast; lymphoblastoid cell line; mitochondrial metabolism; mouse model; novel therapeutic intervention; nucleotide metabolism; post-transplant; programs; senescence; thymidylate; transforming virus; tumor

Abstract Epstein-Barr virus (EBV), the first identified human tumor virus, transforms resting B-cells into rapidly growing lymphoblasts. EBV-driven lymphomas cause significant disease in patients with primary or acquired immunodeficiency, including post-transplantation, with HIV co-infection or with age-related immune-senescence. EBV transforms human B-cells through a program that involves at least three early stages. First, EBV causes major B-cell anabolic remodeling, prior to cell cycle entry. Second, EBV then drives rapid Burkitt-lymphoma (BL) like B-cell growth, triggering cell division every 8-12 hours. Finally, EBV LMP1 and 2A oncoprotein expression cause a transition to lymphoblastoid cell line (LCL)-like growth, where cells divide daily and complete the immortalization program. To achieve this remarkable transition, EBV subverts key host metabolic networks to provide energy, biosynthetic building blocks and protection from reactive oxygen species. Yet, comprehensive approaches have not been used to identify key EBV-targeted mitochondrial metabolic pathways that underlie EBV-mediated B-cell growth transformation. We therefore used multiplexed mass spectrometry to create a temporal proteomic map of EBV-mediated primary human B-cell transformation, and used genome-wide CRISPR screens to identify EBV-induced B-cell dependency factors. These approaches identified a central role for EBV-induced mitochondrial one-carbon (1C) metabolism, an embryonic program that enables rapid cell growth but which is shut off in many adult tissues. Our preliminary data indicates that EBV oncoproteins induce 1C metabolism, including in a mouse model of lymphoproliferative disease. Our central hypothesis is that EBV-induced mitochondrial one-carbon metabolism has critical but distinct roles in each stage of EBV- mediated B-cell growth transformation. Our Specific Aims are therefore to: 1) Identify the role of EBV-induced 1C metabolism in primary B-cell remodeling; (2) Identify the role of one-carbon metabolism in support of rapid Burkitt-like growth; (3) Identify mitochondrial 1C roles in LCL-like cell redox defense. Collectively, these studies are expected to identify how EBV subverts a key embryonic mitochondrial pathway to enable potent growth transformation. 1C metabolism has not been studied in EBV pathogenesis, but is closely related to host enzyme targets blocked by antifolate lymphoma therapies. Our studies may therefore support strategies to develop rational therapeutic regimens to halt EBV-associated malignancies.

抽象的 Epstein-Barr病毒（EBV）是第一个确定的人类肿瘤病毒，将静止的B细胞转化为 快速生长的淋巴细胞。 EBV驱动的淋巴瘤在患有 艾滋病毒共感染或 与年龄相关的免疫染色。 EBV通过一个程序来改变人类B细胞 至少涉及三个早期阶段。首先，EBV引起主要的B细胞合成代谢重塑 细胞周期进入。其次，EBV随后驱动快速伯基特 - 淋巴瘤（BL），如B细胞增长， 每8-12小时触发每8-12小时的细胞分裂。最后，EBV LMP1和2A癌蛋白表达 导致向淋巴母细胞系（LCL）样生长过渡，其中细胞每天分裂，并且 完成永生计划。为了实现这一非凡的过渡，EBV颠覆了密钥 宿主代谢网络可提供能量，生物合成构建块和保护 活性氧。但是，尚未使用全面的方法来识别关键 EBV靶向的EBV靶向线粒体代谢途径是EBV介导的B细胞生长的基础 转型。因此，我们使用多路复用质谱法创建了时间 EBV介导的原代人B细胞转化的蛋白质组学图，并使用了全基因组 CRISPR屏幕以识别EBV诱导的B细胞依赖性因素。这些方法 确定了EBV诱导的线粒体一碳（1C）代谢的核心作用， 胚胎程序可实现快速的细胞生长，但在许多成年组织中被关闭。 我们的初步数据表明EBV癌蛋白诱导1C代谢，包括 淋巴增生性疾病的小鼠模型。我们的中心假设是EBV引起的 线粒体一碳代谢在EBV-的每个阶段都具有关键但独特的作用 介导的B细胞生长转化。因此，我们的具体目的是：1）确定角色 EBV诱导的原代B细胞重塑中的1C代谢； （2）确定一碳的作用 代谢支持快速的伯基特样增长； （3）确定线粒体1c在LCL样中的角色 细胞氧化还原防御。总的来说，这些研究有望确定EBV如何颠覆关键 胚胎线粒体途径可实现有效的生长转化。 1C代谢具有 没有在EBV发病机理中研究，但与被阻塞的宿主酶靶标密切相关 抗叶酸淋巴瘤疗法。因此，我们的研究可能支持发展理性的策略 治疗方案以阻止与EBV相关的恶性肿瘤。