Defining and exploiting EBV-infected cell heterogeneity in non-Hodgkin lymphomas

定义和利用非霍奇金淋巴瘤中 EBV 感染细胞的异质性

• 批准号: 10706553
• 负责人: Micah A. Luftig
• 金额: $ 55.59万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706553
• 关键词: Adult; African Burkitt' s lymphoma; Age; Animal Model; B lymphocyte immortalization; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Behavior; Biological Markers; Cell Separation; Cell model; Cells; Clinical Trials; Coupled; Cytotoxic T-Lymphocytes; DNA Damage; Data; Development; Epstein Barr Virus B cell lymphoma; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Exhibits; Failure; Frequencies; Ganciclovir; Gene Expression; Genetic; Goals; Growth; HIV Infections; Herpesviridae; Heterogeneity; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Human Herpesvirus 4; Immune; Immunosuppression; In Vitro; Individual; Infection; Latent virus infection phase; Lymphoma; Lymphoma cell; Lymphomagenesis; Lytic; Lytic Virus; Mediating; Minor; Modeling; Molecular; Monitor; Non-Hodgkin' s Lymphoma; Oncogenic; Oncogenic Viruses; Organ Transplantation; Outcome; Pathogenesis; Phenotype; Phosphotransferases; Plasmablast; Population; Predisposition; Proliferating; Protein Kinase; Regulation; Repression; Research; Rest; Role; T cell response; Testing; Therapeutic; Therapeutic Intervention; Tumor Tissue; Valganciclovir; Viral; Viral Proteins; Virus; Work; Xenograft Model; cell killing; epstein barr virus mediated immortalization; experimental study; gene product; in vivo; infected B cell; innate immune sensing; large cell Diffuse non-Hodgkin' s lymphoma; latent infection; lymphoblastoid cell line; mouse model; neoplastic cell; novel therapeutics; programs; response; sensor; single-cell RNA sequencing; success; transforming virus; tumor; tumor heterogeneity; tumor progression; tumorigenesis; virtual

Epstein-Barr virus (EBV) was the first human tumor virus discovered over 50 years ago in the context of endemic African Burkitt lymphoma. However, we now know it is also a common herpesvirus that persists as a lifelong latent infection in virtually all adults worldwide. Early work in the field led to a model for EBV infection promoting B-cell lymphomas as evidenced by the growth transformation, or immortalization, of primary resting human B cells into lymphoblastoid cell lines (LCLs). In vivo, EBV latent infection is met with a robust cytotoxic T-cell response keeping most infected individuals protected from the oncogenic potential of the virus. As such, EBV-associated B-cell lymphomas occur at significantly higher rates in the setting of immune suppression. Studies of viral and cellular gene expression in EBV-infected cells in vitro and in vivo have led to a model of lymphomagenesis characterized by the full expression of EBV latency gene products. However, the phenotypes in bulk culture and tumor tissue lack the nuanced detail of cellular heterogeneity and the consequences of minor frequency phenotypes on cancer progression. Our recent single cell RNAseq experiments have characterized gene expression within individual EBV-infected B cells leading to an appreciation of cell fate trajectories and dynamic gene expression behavior of individual cells that we will integrate with human tumor analysis and mouse models of lymphomagenesis. It is our ultimate goal to define the importance of specific EBV-infected cell populations on the progression of B-cell non-Hodgkin lymphomas of the immune suppressed. In this proposal, we aim to define how EBV-infected cell heterogeneity, including innate antiviral restriction and plasmablast differentiation, impacts lymphomagenesis and can be exploited for therapy. Our central hypothesis is that EBV- infected B cells toggle between different states that can restrict or promote lymphomagenesis as well as render cells susceptible to virus-specific therapeutic intervention. We formulated our central hypothesis based on preliminary data including single-cell RNA sequencing of EBV-infected primary B cells early after infection and in LCLs as well as characterization of cell fate dynamics regulating plasmablastic differentiation and lytic reactivation. We also provide evidence supporting a recent clinical trial using the “kick and kill” strategy of promoting EBV lytic reactivation with histone deacetylase inhibition coupled with ganciclovir to kill lymphoma cells that activate viral kinases. Thus, the rationale for the proposed research is that understanding EBV regulation of infected B-cell fates will dissect mechanisms of pathogenesis and reveal new therapeutic avenues to target EBV-positive B-cell lymphomas. We plan to test our central hypothesis and complete the objectives in this proposal through the following three specific aims: i) to define the role of innate immune sensors and effectors in EBV-mediated immortalization and lymphomagenesis, ii) to determine the role of plasmablast differentiation in suppressing EBV-mediated lymphomagenesis, and iii) to define the mechanism by which HDAC inhibition promotes susceptibility of EBV+ DLBCL to killing by ganciclovir.

爱泼斯坦-巴尔病毒（EBV）是50多年前发现的第一个人类肿瘤病毒