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:
  • 金额:
    $ 38.15万
  • 依托单位:
  • 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

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.
项目摘要/摘要 爱泼斯坦-巴尔病毒是包括霍奇金在内的全世界艾滋病相关淋巴瘤(ARL)的重要原因 由EBV潜伏膜蛋白LMP1(CD40模拟物)和LMP2a(A)驱动的淋巴瘤 BCR模拟),结合支持性肿瘤微环境。尽管EBV蛋白EBNA2(它 在EB病毒诱导的B细胞体外转化过程中(表达EBNA2的细胞 有病毒潜伏的“III型”形式,这是高度免疫原性的。因此,大多数感染EBV的人 淋巴瘤(包括接受CART治疗的患者中的ARL)不表达EBNA2。然而,目前还没有 可用于研究EBV感染如何在缺乏EBNA2的情况下导致淋巴瘤的体内或体外模型 唯一的EBV+HL细胞株L591已切换到III型潜伏期。越来越多的证据表明 HIV感染与EBV合作不仅通过诱导免疫抑制,而且通过 创造促炎微环境,促进具有更严格形式的EBV潜伏期的肿瘤 (如HLS中出现的“类型II”形式),不表达EBNA2。我们的实验室已经开发出一种新型的电线 血液人源化小鼠模型,提供高度支持的CD4T细胞丰富的环境,允许 某些EBV突变体在体外被认为是“非转化”的,可以在体内诱导淋巴瘤。我们的新产品 令人兴奋的初步结果显示,一种自然产生的EBNA2缺失的EBV株(P3HR1),即 在体外完全不转化导致表达LMP1和LMP2a的霍奇金样淋巴瘤 模特。此外,我们的初步结果表明,与人类HLS类似,EBNA2诱导的淋巴瘤- 缺失的EBV大量渗透胶原,表达促生存的胶原刺激受体酪氨酸 并激活了PDGFRA和Noch-1信号通路。因此,我们相信我们已经创造了第一个 EB病毒诱导的霍奇金淋巴瘤的活体模型。在这项提案中,我们将剖析EBV蛋白的作用 LMP1和LMP2A以及肿瘤微环境在EBNA2缺失诱导的淋巴瘤中的作用 人源化小鼠的EB病毒。我们假设LMP1和LMP2a,以及CD4T细胞-和胶原- 微环境中的衍生信号是这些淋巴瘤生长所必需的。在目标1中,我们将 野生型(WT)和EBNA2缺失(Akata株)EBV在人源化小鼠中的表型比较 建立模型,并确定旁分泌和/或自分泌信号通路(来源于T细胞、B细胞和/或胶原) 以弥补体内和体外L591 HL细胞中EBNA2表达的缺失。在目标2中,我们将定义 LMP1和LMP2A在肿瘤细胞生长和调节肿瘤微环境中的作用 体内CBH模型和体外L591细胞模型。在目标3中,我们将确定抑制缺口、PDGFRA 和/或DDR1信号通路抑制WT病毒和/或EBNA2缺失病毒诱导的淋巴瘤生长 在人源化小鼠或体外培养的L591细胞中。这些研究的结果应该会为 LMP1和LMP2A促进艾滋病相关霍奇金淋巴瘤的机制(S),并阐明LMP1和LMP2A是如何促进艾滋病相关霍奇金淋巴瘤的 肿瘤微环境与II型潜伏EBV感染协同诱发体内人类淋巴瘤 EBNA2表达已关闭。

项目成果

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Shannon Celeste Kenney其他文献

Shannon Celeste Kenney的其他文献

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{{ truncateString('Shannon Celeste Kenney', 18)}}的其他基金

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
  • 财政年份:
    2023
  • 资助金额:
    $ 38.15万
  • 项目类别:
Project 5 - EBV Drivers of Oncogenesis and Novel Therapies
项目 5 - 肿瘤发生的 EBV 驱动因素和新疗法
  • 批准号:
    10910339
  • 财政年份:
    2023
  • 资助金额:
    $ 38.15万
  • 项目类别:
Effects of EBV Type on Viral Reactivation
EBV 类型对病毒再激活的影响
  • 批准号:
    10386815
  • 财政年份:
    2019
  • 资助金额:
    $ 38.15万
  • 项目类别:
Role of EBV Lytic Infection in Viral Tumorigenesis
EBV 裂解性感染在病毒肿瘤发生中的作用
  • 批准号:
    10428543
  • 财政年份:
    2019
  • 资助金额:
    $ 38.15万
  • 项目类别:
Effects of EBV Type on Viral Reactivation
EBV 类型对病毒再激活的影响
  • 批准号:
    10612828
  • 财政年份:
    2019
  • 资助金额:
    $ 38.15万
  • 项目类别:
Role of EBV Lytic Infection in Viral Tumorigenesis
EBV 裂解性感染在病毒肿瘤发生中的作用
  • 批准号:
    9891040
  • 财政年份:
    2019
  • 资助金额:
    $ 38.15万
  • 项目类别:
Role of EBV Lytic Infection in Viral Tumorigenesis
EBV 裂解性感染在病毒肿瘤发生中的作用
  • 批准号:
    10667423
  • 财政年份:
    2019
  • 资助金额:
    $ 38.15万
  • 项目类别:
Role of EBV Lytic Infection in Viral Tumorigenesis
EBV 裂解性感染在病毒肿瘤发生中的作用
  • 批准号:
    10190848
  • 财政年份:
    2019
  • 资助金额:
    $ 38.15万
  • 项目类别:
Effects of EBV Type on Viral Reactivation
EBV 类型对病毒再激活的影响
  • 批准号:
    9815163
  • 财政年份:
    2019
  • 资助金额:
    $ 38.15万
  • 项目类别:
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
  • 批准号:
    10403940
  • 财政年份:
    2018
  • 资助金额:
    $ 38.15万
  • 项目类别:

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