Metabolic Network Remodeling in Epstein-Barr Virus Lymphomagenesis

EB 病毒淋巴瘤发生中的代谢网络重塑

基本信息

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
项目类别：
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&apos 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&apos 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

项目摘要

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) 是第一个发现的人类肿瘤病毒，可将静息 B 细胞转化为快速生长的淋巴母细胞。 EBV 驱动的淋巴瘤会导致患者罹患严重疾病原发性或获得性免疫缺陷，包括移植后，合并感染艾滋病毒或与年龄相关的免疫衰老。 EBV 通过一个程序转化人类 B 细胞至少涉及三个早期阶段。首先，EBV 会导致主要的 B 细胞合成代谢重塑，然后细胞周期进入。其次，EBV 随后会促进伯基特淋巴瘤 (BL) 类似 B 细胞的快速生长，每 8-12 小时触发一次细胞分裂。最后，EBV LMP1和2A癌蛋白表达导致向类淋巴母细胞系 (LCL) 样生长的转变，其中细胞每天分裂并完成永生计划。为了实现这一非凡的转变，EBV 颠覆了关键宿主代谢网络提供能量、生物合成构件和保护活性氧。然而，尚未采用综合方法来确定关键 EBV 靶向线粒体代谢途径是 EBV 介导的 B 细胞生长的基础转变。因此，我们使用多重质谱法来创建时间 EBV 介导的原代人类 B 细胞转化的蛋白质组图谱，并在全基因组范围内使用 CRISPR 筛选可识别 EBV 诱导的 B 细胞依赖性因子。这些方法确定了 EBV 诱导的线粒体一碳 (1C) 代谢的核心作用，胚胎程序使细胞能够快速生长，但在许多成体组织中被关闭。我们的初步数据表明 EBV 癌蛋白诱导 1C 代谢，包括在淋巴细胞增殖性疾病小鼠模型。我们的中心假设是 EBV 诱导线粒体一碳代谢在 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，我们的具体目标是： 1) 确定角色原代 B 细胞重塑中 EBV 诱导的 1C 代谢的研究； (2) 识别一碳的作用支持快速伯基特生长的新陈代谢； (3) 鉴定线粒体 1C 在 LCL 样中的作用细胞氧化还原防御。总的来说，这些研究有望确定 EBV 如何颠覆一个关键因素胚胎线粒体途径以实现有效的生长转化。 1C 代谢有尚未在 EBV 发病机制中进行研究，但与 EBV 阻断的宿主酶靶点密切相关抗叶酸淋巴瘤治疗。因此，我们的研究可能支持制定合理的策略阻止 EBV 相关恶性肿瘤的治疗方案。