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Role of Epstein-Barr virus LMP2A protein in maintaining oncogenic IgM signaling in EBV+ B cell lymphomas

Epstein-Barr病毒LMP2A蛋白在维持EBV B细胞淋巴瘤中致癌IgM信号传导中的作用

基本信息

批准号：
10540952
负责人：
ERIC C JOHANNSEN
金额：
$ 43.65万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10540952
关键词：
Antibodies Antigens Automobile Driving B Cell Proliferation B-Cell Antigen Receptor B-Cell Lymphomas B-Lymphocytes BLNK gene Characteristics Clinical Complex Cytotoxic Chemotherapy Data Dependence Development Diffuse Large-Cell Lymphoma Drug resistance Epstein-Barr Virus Infections Failure Gene Expression Growth HIV Hodgkin Disease Human Herpesvirus 4 Immunocompromised Host Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Isotypes Immunoglobulin M Impairment In Vitro Individual Knowledge Lymphocyte Activation Lymphoma Lymphomagenesis Mediating Mediator of activation protein Morbidity - disease rate Non-Hodgkin&apos s Lymphoma Oncogenes Oncogenic Outcome Pathway interactions Persons Pharmaceutical Preparations Pharmacology Plasma Cells Play Predisposition Process Proteins Receptor Signaling Resistance Role Signal Pathway Signal Transduction Signaling Molecule Testing Therapeutic Therapeutic Intervention Tissue-Specific Gene Expression Ursidae Family Viral Viral Oncogene antiretroviral therapy cell transformation clinical predictors design high risk humanized mouse improved in vivo infected B cell inhibitor lymphoblastoid cell line mortality mutant novel response stem targeted agent targeted treatment transforming virus tumorigenesis

项目摘要

PROJECT SUMMARY Epstein-Barr virus (EBV) causes a wide spectrum of lymphomas including Hodgkin, Burkitt, and diffuse large cell lymphomas (DLBCL). The proportion of EBV+ lymphomas rises sharply as does morbidity and mortality in HIV-infected persons despite combined antiretroviral therapy (cART), suggesting specific failure to control viral driven lymphomas. However, the mechanistic processes contributing to EBV-driven lymphomagenesis remain poorly understood. This proposal will investigate a conceptually novel hypothesis that the LMP2A viral oncogene interacts with the B cell receptor (BCR), serving to maintain it in its growth promoting IgM isotype. This hypothesis predicts that EBV transformed cells expressing LMP2A are dependent upon their constitutive activation of cellular mediators of antigen-induced signaling, and thus will be susceptible to agents that target this signaling cascade, whereas EBV-transformed cells that do not express LMP2A will be resistant to such drugs. Our proposal stems from two exciting observations that we have made about lymphoblastoid cells (LCLs) transformed by an EBV mutant that lacks LMP2A (∆LMP2A-EBV). First, we discovered that, unlike normal LCLs, the growth of ∆LMP2A-LCLs is not dependent on mediators of antigen-induced signaling like BLNK and BTK. Second, in contrast to normal LCLs, ∆LMP2A-LCLs fail to maintain the growth promoting IgM form of the BCR and instead express the IgG-BCR. Since antigen signaling through IgG-BCR promotes differentiation into plasma cells which secrete high levels of antibodies but have limited proliferative potential, our central hypothesis is that LMP2A contributes to lymphomagenesis by facilitating outgrowth of EBV transformed B lymphocytes expressing the growth promoting IgM-BCR. This proposal will analyze mechanistic pathways and gene expression profiles in EBV-transformed LCLs and test lymphoma formation in humanized mice in order to distinguish the direct contributions of LMP2A from those mediated by the IgM-BCR, and assess the therapeutic vulnerability that arise from each. Specifically, we will (1) Investigate intersection of LMP2A and BCR Ig isotype on B lymphocyte transformation, (2) Characterize impact of antigenic stimulation in the presence or absence of LMP2A expression, and (3) Determine LMP2A-mediated susceptibility to therapeutic inhibition of signaling molecules. Together these studies provide a framework for how LMP2A interacts with the BCR to promote EBV transformation and provide new opportunities for therapeutic intervention in EBV-associated lymphomas.

项目总结