Epstein-Barr virus LMP1 mediated oncogenicity

EB 病毒 LMP1 介导的致癌性

• 批准号: 10676959
• 负责人: Benjamin Elison Gewurz
• 金额: $ 40.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676959
• 关键词: AIDS-Related Lymphoma; Acquired Immunodeficiency Syndrome; Address; African Burkitt' s lymphoma; Automobile Driving; B lymphoid malignancy; B-Lymphocytes; Binding; CRISPR screen; Cells; Central Nervous System Lymphoma; Cessation of life; ChIP-seq; Chromatin Loop; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA; Data; Dependence; Development; Disease; Elderly; Enhancers; Epigenetic Process; Epstein-Barr Virus Nuclear Antigens; Epstein-Barr Virus latency; Genes; Genomics; Goals; Growth; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Hodgkin Disease; Human; Human Herpesvirus 4; IRF4 gene; Immunocompromised Host; Individual; LMP1; Large-Cell Immunoblastic Lymphoma; Licensing; Lymphomagenesis; Lymphoproliferative Disorders; MYC gene; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mediating; Membrane Proteins; Modeling; NF-kappa B; Nuclear; Nuclear Antigens; Nuclear Translocation; Oncogenes; Oncogenic; Oncogenic Viruses; Oncoproteins; Population; Proteomics; Rest; Risk; Role; Site; Therapeutic; Transcription Factor AP-1; Viral; Viral Oncogene; Viral Proteins; Virus; Virus Activation; antagonist; c-myc Genes; cancer cell; cell growth; cell transformation; chaperonin; cofactor; gammaherpesvirus; genome-wide; infected B cell; insight; large cell Diffuse non-Hodgkin' s lymphoma; lymphoblastoid cell line; mortality; novel; novel therapeutic intervention; nuclear reprogramming; post-transplant; programs; promoter; restraint; therapeutic target; transcription factor; transcriptome sequencing; transforming virus

Abstract Gamma-herpesvirus-driven lymphoproliferative disorders cause significant mortality in HIV+ populations. Despite highly active antiretroviral therapy, HIV+ individuals remain at elevated risk for Epstein-Barr virus (EBV)-associated B-cell cancers. EBV is identified in >40% of immunoblastic diffuse large B-cell lymphomas and nearly 100% of Hodgkin lymphoma and primary central nervous system lymphomas in HIV+ individuals. EBV transforms human B-cells into lymphoblastoid cell lines (LCL), a major model of EBV-driven immunoblastic lymphomas of immunosuppressed hosts. Yet, key EBV-induced host dependency factors remain to be elucidated. We therefore used systematic approaches to gain insights into key EBV oncoprotein targets. We used: 1) Genome-wide CRISPR screens to identify host dependency factors downstream of EBV oncoproteins; 2) Multiplexed mass spectrometry to create a proteomic map of EBV-mediated B-cell transformation; and 3) ChIP-seq to identify EBV oncoprotein host genomic targets, which found the first viral super-enhancers (SE), comprised of 5 LMP1- activated NF-kB and 4 EBV nuclear antigen subunits. These converged on the transcription factors BATF, IRF4 and IRF2 as key LMP1-targeted host dependency factors. Our preliminary studies indicate that BATF/IRF4 and IRF2 complexes have key dependency factor roles in EBV oncoprotein-driven MYC expression, necessary for LCL growth and survival. We propose to define how the interplay between viral oncoprotein superenhancers, BATF/IRF4 and IRF2 complexes drive MYC expression in lymphoblastoid B-cells. Our Specific Aims are to (1) Identify how EBV oncoproteins activate dependency factor BATF/IRF4 complexes to induce MYC; (2) Identify key BATF/IRF4 roles in EBV oncoprotein-induced MYC induction in lymphoblastoid B-cells; and (3) Identify how the viral SE-driven dependency factor IRF2 is necessary to support lymphoblastoid cell MYC expression. These studies specifically address PA-16-426 by advancing understanding of development, progression and treatment of malignancies observed in individuals with underlying HIV infection. The proposed studies are expected to contribute to understanding of how EBV oncoproteins and key genetically-defined downstream host dependency factors reprogram lymphoblastoid cell MYC expression. EBV oncoproteins may not be druggable, but SE and IRF4 are increasingly therapeutic targets. Since viral oncoprotein-induced MYC expression is critical for EBV-transformed B-cell growth, the longterm goal of these studies is to support rational approaches to restrain viral oncogene subversion of MYC.

抽象的 γ-疱疹病毒驱动的淋巴增生性疾病在HIV+中引起显着死亡率 人群。尽管高活性抗逆转录病毒疗法，HIV+个体仍处于较高的风险 用于爱泼斯坦 - 巴尔病毒（EBV）相关的B细胞癌。 EBV在> 40％的> 40％ 免疫细胞弥漫性大B细胞淋巴瘤和霍奇金淋巴瘤的近100％和 HIV+个体中的原发性中枢神经系统淋巴瘤。 EBV转换人类B细胞 进入淋巴母细胞系（LCL），这是EBV驱动的免疫细胞淋巴瘤的主要模型 免疫抑制的宿主。但是，关键EBV引起的主机依赖性因素仍然是 阐明。因此，我们使用系统的方法来洞悉关键EBV癌蛋白 目标。我们使用：1）全基因组CRISPR屏幕识别宿主依赖性因素 EBV癌蛋白的下游； 2）多路复用质谱法以创建蛋白质组学图 EBV介导的B细胞转换； 3）chip-seq识别EBV癌蛋白宿主 基因组靶标发现了第一个病毒性超增强剂（SE），由5 lmp1-组成 活化的NF-KB和4个EBV核抗原亚基。这些在转录上汇合 BATF，IRF4和IRF2作为关键LMP1靶向宿主依赖性因素的因素。我们的初步 研究表明，BATF/IRF4和IRF2复合物在EBV中具有关键的依赖性因子角色 癌蛋白驱动的MYC表达，对于LCL生长和生存所必需。我们建议 定义病毒癌蛋白超蛋白超蛋白，BATF/IRF4和IRF2之间的相互作用如何 复合物在淋巴母细胞B细胞中驱动MYC表达。我们的具体目的是（1） 确定EBV癌蛋白如何激活依赖性因子BATF/IRF4复合物诱导 妈妈（2）在EBV Oncopotin诱导的MYC诱导中确定关键的BATF/IRF4角色 淋巴母细胞B细胞； （3）确定病毒SE驱动的依赖性因子IRF2是如何 支持淋巴母细胞MYC表达所必需的。这些研究专门针对 PA-16-426通过促进对发展，进步和治疗的理解 在潜在的HIV感染的个体中观察到的恶性肿瘤。拟议的研究是 有望有助于理解EBV癌蛋白和关键遗传定义 下游宿主依赖因子重编程淋巴母细胞MYC表达。 EBV 癌蛋白可能无法吸毒，但是SE和IRF4是越来越多的治疗靶标。自从 病毒癌蛋白诱导的MYC表达对于EBV转换的B细胞生长至关重要， 这些研究的长期目标是支持限制病毒癌基因的理性方法 颠覆MYC。