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.

项目摘要爱泼斯坦 - 巴尔病毒（EBV）引起广泛的淋巴瘤，包括霍奇金，伯基特和弥漫细胞淋巴瘤（DLBCL）。 EBV+淋巴瘤的比例急剧上升艾滋病毒感染者合并抗逆转录病毒疗法（CART），表明特定的无法控制病毒驱动的淋巴瘤。但是，导致EBV驱动的淋巴作用的机械过程仍然存在理解不佳。该提议将调查一个概念上新的假设，即LMP2A病毒癌基因与B细胞受体（BCR）相互作用，以维持其生长促进IgM同种型。这一假设预测EBV转化表达LMP2A的细胞取决于其本构激活抗原诱导的信号传导的细胞介质，因此将易于靶向的药物该信号级联反应，而不表达LMP2A的EBV转换细胞将对这种抗性毒品。我们的提议源于我们对淋巴母细胞的两个令人兴奋的观察结果（LCL）由缺少LMP2A（∆LMP2A-EBV）的EBV突变体转换。首先，我们发现这与正常LCLS，∆LMP2A-LCLS的生长不取决于抗原诱导的信号传导的介体 Blnk和BTK。第二，与正常LCL相比，∆LMP2A-LCLS无法维持促进IgM的生长 BCR的形式，而是表达IgG-BCR。由于通过IgG-BCR的抗原信号促进分化为浆细胞分泌高水平的抗体但具有有限的增殖潜力，我们的中心假设是LMP2A通过促进EBV的生长来促进淋巴作用转化的B淋巴细胞表达了促进IgM-BCR的生长。该建议将分析机械 EBV转化的LCLS中的途径和基因表达谱，并在人源化中测试淋巴瘤形成为了区分LMP2A的直接贡献与IGM-BCR介导的小鼠的直接贡献，以及评估每个人都会产生的治疗脆弱性。具体而言，我们将（1）调查 LMP2A和BCR Ig同种型在B淋巴细胞转化上，（2）表征了抗原刺激在 LMP2A表达的存在或不存在，（3）确定LMP2A介导的易感性信号分子的治疗抑制。这些研究共同为LMP2A提供了一个框架与BCR互动以促进EBV转型并为治疗提供新的机会干预与EBV相关的淋巴瘤。