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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.

eb病毒（EBV）是一种与多种癌症相关的致癌疱疹病毒，包括伯基特癌