Roles of LMP1 and MYC in EBV-induced B-cell tumors

LMP1 和 MYC 在 EBV 诱导的 B 细胞肿瘤中的作用

• 批准号: 10749776
• 负责人: Shannon Celeste Kenney
• 金额: $ 45.12万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749776
• 关键词: B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; Biological Models; Burkitt Lymphoma; Cell Culture Techniques; Cell Line; Cells; DNA Methylation; DNA Methylation Inhibition; DNMT3B gene; Development; EBNA2 protein; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Epstein-Barr Virus-Related Lymphoma; Gene Mutation; Genes; Genetic Transcription; Growth; HIV Infections; Hodgkin Disease; Human; Human Herpesvirus 4; Immune response; Immunocompetent; Immunocompromised Host; In Vitro; LMP1; Lymphoma; MYC gene; Mediating; Modeling; Mus; Oncogenic Viruses; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Proteins; RNA; Retroviral Vector; Retroviridae; Role; Structure of germinal center of lymph node; System; T cell response; T-Lymphocyte; TNFSF5 gene; Testing; Time; Tonsil; Umbilical Cord Blood; Viral; Viral Proteins; Virus Latency; anti-tumor immune response; experimental study; humanized mouse; immunogenic; immunosuppressed; in vitro Model; in vivo; in vivo Model; infected B cell; interleukin-21; large cell Diffuse non-Hodgkin' s lymphoma; mouse model; mutant; neoplastic cell; novel; overexpression; promoter; public health relevance; restoration; small molecule; stable cell line; transcription factor; transforming virus; tumor; viral RNA

PROJECT SUMMARY/ABSTRACT Epstein-Barr virus (EBV) is an important cause of human lymphomas in both immunocompetent and immunosuppressed humans, including Burkitt lymphomas (BLs), Hodgkin lymphomas (HLs) and diffuse large B cell lymphomas (DLBCLs). There are three different types of EBV latency (types I, II and III) that differ in the number of latent viral proteins expressed and transforming ability. Only type III viral latency (in which all 9 latent viral proteins are expressed) can transform primary human B cell in vitro, but because type III latency is highly immunogenic, EBV+ tumors with type III latency in humans are relatively rare and largely found in immunosuppressed hosts. EBV+ HLs and DLBCLs in humans commonly have type II latency (characterized by expression of EBNA1, LMP1 and LMP2A), while EBV+ BLs, which contain MYC translocations, have type I latency (in which EBNA1 is the only viral protein expressed). However, there is currently no in vivo or in vitro model available to study how EBV infection causes lymphomas with type I or type II latency, since this form of viral latency is not transforming in vitro and wild-type EBV-induced lymphomas in humanized mouse models inevitably support type III latency. EBNA2 transcriptionally activates each of the latent viral promoters used during type III latency. Using a newly constructed EBNA2-deleted EBV mutant (ΔEBNA2 EBV) made by our lab, we have developed a novel culture system that allows us to stably infect primary naïve B cells in vitro with this mutant, and to examine the effect of MYC over-expression. Our exciting preliminary results show that B cells infected with ΔEBNA2 EBV form DLBCL-like and HL-like tumors with type II viral latency at late time points in NSG mice, and that over-expressing the MYC gene (using a retroviral vector) in ΔEBNA2 EBV-infected B cells results in rapid onset of aggressive tumors that resemble human BLs and support type I EBV latency. In contrast, expression of MYC alone does not cause tumors in this model. As human BLs, DLBCLs and HLs are derived from germinal center (GC) B cells, in Aim 1, we will use this new model to examine the ability of ΔEBNA2 EBV- infected primary GC B cells (with or without MYC over-expression) to form lymphomas in NSG mice. In Aim 2, we will identify the specific EBV genes (and/or viral RNAs) required for the development of ΔEBNA2 EBV- induced tumors (with or without MYC) in naïve versus GC B cells. In Aim 3, we will define mechanisms by which MYC turns off LMP1 expression in ΔEBNA2 EBV-induced lymphomas and determine if small molecules that can restore LMP1 expression enhance the immune response to tumors in humanized mice. The proposed experiments will provide the first model system to define how types I and II EBV latency cause lymphomas in human GC B cells and to ask if restoration of LMP1 expression in BLs enhances the host immune response.

项目总结/文摘