B cell determinants of EBV latency

EBV 潜伏期的 B 细胞决定因素

基本信息

批准号：
10701826
负责人：
ETHEL CESARMAN
金额：
$ 82.78万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-09 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10701826
关键词：
3-Dimensional AIDS-Related Diffuse Large B-cell Lymphoma AIDS-Related Lymphoma Acquired Immunodeficiency Syndrome Address Affect B cell differentiation B lymphocyte immortalization B-Cell Development B-Cell Lymphomas B-Lymphocytes BCL6 gene Biology Burkitt Lymphoma Cell Compartmentation Cells Cellular biology Central Nervous System Lymphoma ChIP-seq Chromatin Classification Clustered Regularly Interspaced Short Palindromic Repeats Cues Cytometry Cytosine DNA DNA Modification Methylases DNMT3B gene Development Down-Regulation Enzymes Epigenetic Process Epstein Barr Virus B cell lymphoma Epstein-Barr Virus Infections Epstein-Barr Virus latency Epstein-Barr Virus-Related Lymphoma Epstein-Barr Virus-Related Malignant Neoplasm Event Exhibits Family Foundations Frequencies Future Gene Silencing Genes Genetic Genetic Transcription Genome Grant HIV Herpesviridae Heterogeneity Histologic Histone H1 Histones Hodgkin Disease Human Human Herpesvirus 4 Image Immune Immunocompetent Immunologics Infection Integration Host Factors Intrinsic factor Knowledge LMP1 Large-Cell Immunoblastic Lymphoma Lead Learning Link Lymphoma Lymphomagenesis Lymphoproliferative Disorders Maintenance Malignant - descriptor Malignant Neoplasms Mediating Memory Methylation Methyltransferase Mexico Modeling Molecular Mutate Mutation Mutation Analysis Oncogenic Oncogenic Viruses Oncoproteins PRC1 Protein Patients Pattern Persons Protein Isoforms Proteomics Recurrence Regulation Role STAT3 gene Sampling Signal Transduction Site Structure of germinal center of lymph node T-Cell Immunodeficiency Tumor-Derived Ubiquitination Untranslated RNA Variant Viral Viral Genome Viral Proteins Virus Virus Latency Work antiretroviral therapy cDNA Expression cancer genome chemical genetics co-infection cohort cytokine derepression driver mutation epigenome genetic analysis genetic manipulation high risk histone methyltransferase infected B cell interleukin-21 large cell Diffuse non-Hodgkin&apos s lymphoma latent gene expression loss of function mutation lytic gene expression multiple omics neoplastic cell novel therapeutic intervention post-transplant pressure primary effusion lymphoma programs promoter recruit superinfection tumor viral DNA viral genomics virology

项目摘要

Epstein-Barr virus (EBV) is an oncogenic herpesvirus associated with multiple cancers, including Burkitt lymphoma, Hodgkin lymphoma, primary central nervous system lymphoma and post-transplant lymphomas. EBV-associated B-cell lymphomas occur at significantly higher frequency in the setting of HIV co-infection, even with the use of antiretroviral therapy. AIDS-related lymphomas (ARLs) are most commonly diffuse large B cell lymphomas (DLBCLs), followed by Burkitt lymphoma and classical Hodgkin lymphoma (cHL), all frequently associated with EBV infection. Each of these cancers is linked to a viral latency program that is used as EBV- infected B-cells navigate the B-cell compartment to colonize memory cells, the reservoir for lifelong infection. Yet, much remains to be learned about epigenetic mechanism that control viral oncoprotein expression, and how this can ultimately be exploited in novel therapeutic approaches. We therefore recently performed CRISPR and chemical genetic analysis to identify host factors that tightly regulate the expression of EBV oncoproteins in B-cells. These analyses highlighted host DNA and histone methyltransferases with key roles in regulation of EBV latency and lytic gene expression. Characterization of top screen hits revealed multiple layers of EBV oncoprotein control, yet, how DNA and histone methyltransferases target specific EBV genomic promoter sites remains largely unknown. In parallel, we integrated these studies with tumor genome mutation analysis to identify host genes that are mutated at high frequency in EBV-infected and EBV-uninfected B-cell lymphomas. These analyses recently identified that linker H1 histone genes, which are highly recurrent in B cell lymphomas, are genetic driver mutations in lymphomagenesis. They also demonstrated that histone H1 mutation drives malignant transformation via three-dimensional genome reorganization, resulting in epigenetic reprogramming and de-repression of developmentally silenced genes. Notably, our proteomic analysis identified that EBV strongly downmodulates expression of multiple linker histone 1 isoforms, though it remains unknown how this H1 subversion alters the viral and host genome landscape in EBV-associated lymphomas. We hypothesize that germinal center microenvironment cues orchestrate B-cell epigenetic programs that together with EBV oncoprotein effects on linker histone expression dictate tumor latency programs. While immunological selective pressures also contribute to latency, we propose that T-follicular helper signals and cell intrinsic factors control EBV latency patterns. Our specific aims are therefore to: 1) Identify how key germinal center cytokines affect epigenetic writers to alter the EBV epigenome and dictate latency program selection. 2) Identify dynamic histone H1 roles in EBV epigenome and latency program regulation. 3) Define the relationship between B-cell differentiation state, epigenetic profile, and EBV latency pattern in HIV+ DLBCL. Collectively, these studies address long-standing question in the EBV tumor virology field and lay the foundation for novel therapeutic approaches to EBV-driven human malignancies.

Epstein-Barr 病毒 (EBV) 是一种致癌性疱疹病毒，与多种癌症相关，包括 Burkitt 淋巴瘤、霍奇金淋巴瘤、原发性中枢神经系统淋巴瘤和移植后淋巴瘤。在 HIV 合并感染的情况下，EBV 相关 B 细胞淋巴瘤的发生频率明显更高，即使使用抗逆转录病毒治疗。艾滋病相关淋巴瘤 (ARL) 最常见的是弥漫性大 B 型淋巴瘤细胞淋巴瘤 (DLBCL)，其次是伯基特淋巴瘤和经典霍奇金淋巴瘤 (cHL)，所有这些都很常见与EB病毒感染有关。这些癌症中的每一种都与病毒潜伏程序有关，该程序被用作 EBV- 受感染的 B 细胞在 B 细胞区室中导航，定植记忆细胞，这是终生感染的储存库。然而，关于控制病毒癌蛋白表达的表观遗传机制还有很多东西有待了解，最终如何在新的治疗方法中利用这一点。因此我们最近执行了 CRISPR 和化学遗传分析可识别严格调控 EBV 表达的宿主因子 B 细胞中的癌蛋白。这些分析强调了宿主 DNA 和组蛋白甲基转移酶在 EBV 潜伏期和裂解基因表达的调节。热门屏幕点击的特征揭示了多个 EBV 癌蛋白控制层，然而，DNA 和组蛋白甲基转移酶如何靶向特定 EBV 基因组启动子位点仍然很大程度上未知。与此同时，我们将这些研究与肿瘤基因组突变相结合分析以确定在 EBV 感染和未感染 EBV 的 B 细胞中高频突变的宿主基因淋巴瘤。这些分析最近发现，连接子 H1 组蛋白基因在 B 细胞淋巴瘤是淋巴瘤发生中的基因驱动突变。他们还证明组蛋白 H1 突变通过三维基因组重组驱动恶性转化，导致表观遗传发育沉默基因的重编程和去抑制。值得注意的是，我们的蛋白质组分析发现 EBV 强烈下调多个接头组蛋白 1 亚型的表达，尽管它仍然存在目前尚不清楚这种 H1 颠覆如何改变 EBV 相关淋巴瘤中的病毒和宿主基因组景观。我们假设生发中心微环境线索协调 B 细胞表观遗传程序与 EBV 癌蛋白对接头组蛋白表达的影响一起决定了肿瘤潜伏期程序。虽然免疫选择压力也会导致潜伏期，但我们建议滤泡 T 细胞辅助信号和细胞内在因素控制 EBV 潜伏期模式。因此，我们的具体目标是：1) 确定关键的生发中心细胞因子如何影响表观遗传作家，从而改变 EBV 表观基因组并决定延迟程序选择。 2) 确定动态组蛋白 H1 在 EBV 表观基因组和潜伏期程序中的作用规定。 3) 定义B细胞分化状态、表观遗传特征和EBV潜伏期之间的关系 HIV+ DLBCL 的模式。总的来说，这些研究解决了 EBV 肿瘤病毒学中长期存在的问题领域并为 EB 病毒驱动的人类恶性肿瘤的新治疗方法奠定基础。