B cell determinants of EBV latency

点击翻译按钮获取中文摘要

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.