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EBV LMP1/LMP2A Proteins Promote Hodgkin-like Lymphomas in Humanized Mice

EBV LMP1/LMP2A 蛋白促进人源化小鼠霍奇金样淋巴瘤的发生

基本信息

批准号：
10152365
负责人：
Shannon Celeste Kenney
金额：
$ 38.15万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-13 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152365
关键词：
AIDS-Related Hodgkin&apos s Lymphoma AIDS-Related Lymphoma Acquired Immunodeficiency Syndrome Attenuated Autocrine Communication Automobile Driving B-Cell Antigen Receptor B-Cell Lymphomas B-Lymphocytes CD4 Positive T Lymphocytes Cell Line Cells Collagen DDR1 gene Development EBNA2 protein Environment Epstein-Barr Virus Infections Epstein-Barr Virus latency Goals Growth HIV Infections Hodgkin Disease Human Human Herpesvirus 4 Immunocompetence Immunocompromised Host Immunosuppression In Vitro Inflammatory LMP1 Laboratories Lead Lymphoma Lymphoma cell Malignant Neoplasms Membrane Proteins Modeling PDGFA gene PDGFRA gene Paracrine Communication Pathway interactions Patients Phenotype Proteins Receptor Protein-Tyrosine Kinases Research Role Signal Pathway Signal Transduction T-Lymphocyte TNFRSF5 gene Transcription Coactivator Tumor-Derived Umbilical Cord Blood Viral Proteins Virus Virus Latency cell growth humanized mouse immunogenic improved in vitro Model in vivo in vivo Model insight mouse model mutant neoplastic cell notch protein novel novel therapeutics overexpression public health relevance tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT Epstein-Barr virus is an important cause of AIDS-related lymphomas (ARLs) world-wide, including Hodgkin lymphomas (HLs) that are driven by the EBV latent membrane proteins LMP1 (a CD40 mimic) and LMP2A (a BCR mimic), in conjunction with a supportive tumor microenvironment. Although the EBV protein EBNA2 (which mimics notch signaling) is required for EBV-induced transformation of B cells in vitro, cells that express EBNA2 have the “type III” form of viral latency, which is highly immunogenic. Thus, most EBV-infected human lymphomas (including ARLs in cART-treated patients) do not express EBNA2. However, there is currently no in vivo or in vitro model available to study how EBV infection can cause lymphomas in the absence of EBNA2 expression, and the only EBV+ HL cell line, L591, has switched to type III latency. Increasing evidence suggests that HIV infection collaborates with EBV to induce lymphomas not only by inducing immunosuppression, but by creating a pro-inflammatory microenvironment that promotes tumors with more stringent forms of EBV latency (such as the “type II” form that occurs in HLs) that do not express EBNA2. Our lab has developed a novel cord blood-humanized mouse model which provides a highly supportive CD4 T cell-rich environment that allows certain EBV mutants previously considered “non-transforming” in vitro to induce lymphomas in vivo. Our new exciting preliminary results reveal that a naturally occurring EBNA2-deleted EBV strain (P3HR1) that is completely non-transforming in vitro causes Hodgkin-like lymphomas that express LMP1 and LMP2A in this model. Furthermore, our preliminary results suggest that similar to human HLs, lymphomas induced by EBNA2- deleted EBV are heavily infiltrated with collagen, express the pro-survival collagen-stimulated receptor tyrosine kinase DDR1, and have activated PDGFRA and notch-1 signaling. Thus, we believe we have created the first in vivo model for EBV-induced Hodgkin lymphoma. In this proposal, we will dissect the roles of the EBV proteins LMP1 and LMP2A, as well as the tumor microenvironment, in driving lymphomas induced by EBNA2-deleted EBV in humanized mice. We hypothesize that both LMP1 and LMP2A, as well as CD4 T cell- and collagen- derived signals in the microenvironment, are required for the growth of these lymphomas. In Aim 1, we will compare the phenotypes of wild-type (WT) versus EBNA2-deleted (Akata strain) EBV in humanized mouse models, and identify paracrine and/or autocrine signaling pathways (derived from T cells, B cells and/or collagen) that compensate for loss of EBNA2 expression both in vivo and in L591 HL cells in vitro. In Aim 2, we will define the roles of LMP1 and LMP2A on tumor cell growth, and in regulating the tumor microenvironment, in both the CBH model in vivo and in L591 cells in vitro. In Aim 3, we will determine whether inhibiting notch, PDGFRA and/or DDR1 signaling attenuates the growth of lymphomas induced by WT virus and/or EBNA2-deleted virus in humanized mice or in L591 cells in vitro. The results of these studies should provide key insights into the mechanism(s) by which LMP1 and LMP2A promote AIDS-related Hodgkin lymphomas, and elucidate how the tumor microenvironment cooperates with type II latent EBV infection to induce human lymphomas in vivo when EBNA2 expression is shut off.

项目总结/文摘