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:
  • 金额:
    $ 43.65万
  • 依托单位:
  • 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

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

项目成果

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ERIC C JOHANNSEN其他文献

ERIC C JOHANNSEN的其他文献

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{{ truncateString('ERIC C JOHANNSEN', 18)}}的其他基金

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
  • 批准号:
    10707312
  • 财政年份:
    2022
  • 资助金额:
    $ 43.65万
  • 项目类别:
Epigenetic determinants of Epstein-Barr virus and cellular DNA in oral diseases
口腔疾病中 Epstein-Barr 病毒和细胞 DNA 的表观遗传决定因素
  • 批准号:
    8737880
  • 财政年份:
    2013
  • 资助金额:
    $ 43.65万
  • 项目类别:
Epigenetic determinants of Epstein-Barr virus and cellular DNA in oral diseases
口腔疾病中 Epstein-Barr 病毒和细胞 DNA 的表观遗传决定因素
  • 批准号:
    8625514
  • 财政年份:
    2013
  • 资助金额:
    $ 43.65万
  • 项目类别:
Epigenetic determinants of Epstein-Barr virus and cellular DNA in oral diseases
口腔疾病中 Epstein-Barr 病毒和细胞 DNA 的表观遗传决定因素
  • 批准号:
    8894306
  • 财政年份:
    2013
  • 资助金额:
    $ 43.65万
  • 项目类别:
Epigenetic determinants of Epstein-Barr virus and cellular DNA in oral diseases
口腔疾病中 Epstein-Barr 病毒和细胞 DNA 的表观遗传决定因素
  • 批准号:
    9113554
  • 财政年份:
    2013
  • 资助金额:
    $ 43.65万
  • 项目类别:
Epigenetic determinants of Epstein-Barr virus and cellular DNA in oral diseases
口腔疾病中 Epstein-Barr 病毒和细胞 DNA 的表观遗传决定因素
  • 批准号:
    9318496
  • 财政年份:
    2013
  • 资助金额:
    $ 43.65万
  • 项目类别:
EBNA-3C in B Lymphocyte Transformation by EBV
EBNA-3C 在 EBV 转化 B 淋巴细胞中的作用
  • 批准号:
    6618097
  • 财政年份:
    2001
  • 资助金额:
    $ 43.65万
  • 项目类别:
EBNA-3C in B Lymphocyte Transformation by EBV
EBNA-3C 在 EBV 转化 B 淋巴细胞中的作用
  • 批准号:
    6532875
  • 财政年份:
    2001
  • 资助金额:
    $ 43.65万
  • 项目类别:
EBNA-3C in B Lymphocyte Transformation by EBV
EBNA-3C 在 EBV 转化 B 淋巴细胞中的作用
  • 批准号:
    6360398
  • 财政年份:
    2001
  • 资助金额:
    $ 43.65万
  • 项目类别:
Core C - Virus Core
核心 C - 病毒核心
  • 批准号:
    10414882
  • 财政年份:
    1997
  • 资助金额:
    $ 43.65万
  • 项目类别:

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