Pathways of Death and Survival in EBV B Cell Lymphomas

EBV B 细胞淋巴瘤的死亡和生存途径

• 批准号: 7101901
• 负责人: Olivia M Martinez
• 金额: $ 25.62万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-07 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101901
• 关键词: AP1 protein; B cell lymphoma; CD95 molecule; DNA binding protein; Epstein Barr virus; JAK kinase; SDS polyacrylamide gel electrophoresis; apoptosis; biological signal transduction; gel mobility shift assay; gene deletion mutation; gene expression; human subject; interleukin 10; latent virus infection; mutant; nuclear factor kappa beta; point mutation; protein protein interaction; virus genetics; virus infection mechanism; virus protein

DESCRIPTION (provided by applicant): Epstein Barr virus (EBV) is a gammaherpes virus that is associated with multiple human malignancies including Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, some non-Hodgkin's lymphomas, and B cell lymphomas in bone marrow and solid organ recipients and patients with AIDS. In immunosuppressed and immunocompromised individuals the prevailing view is that impaired cellular immunity permits uncontrolled expansion of EBV-infected B cells. However, alterations in EBV-infected B cells that provide growth and survival advantages could also contribute to lymphomagenesis. Accordingly, we have demonstrated that EBV-infected B cell lines established from patients with post-transplant lymphoproliferative disorder (LPD) have constitutive activation of the Jak/STAT signal transduction pathway that is associated with cytokine-mediated cellular growth. In addition, the EBV-infected B cell lines show marked resistance to induction of apoptosis through the Fas/Fas ligand and TRAIL/DR pathways. Importantly, establishment of a latent EBV infection is sufficient to confer resistant to previously sensitive cells. Moreover, resistance to Fas-induced apoptosis correlates with expression of the natural LMP1 variants associated with increased AP-1 activation. The long-term objectivity of this work is to understand how EBV promotes the growth and survival of EBV-associated B cell lymphomas. The hypothesis is that natural LMP1 variants have differential ability to modulate pathways of apoptosis. Further, we hypothesize that LMP1 associates with Jak kinases and is sufficient for STAT activation and IL-10 production. Specific Aim 1 will determine the capacity of natural LMP1 variants to protect from intrinsic and extrinsic apoptotic stimuli. The ability of LMP1 variants to activate NFKappaB, AP-1 and modulate death receptor proximal and downstream regulators of apoptosis will be determined. Specific Aim 2 will determine the role of LMP1, and its natural variants, in activation of the Jak/STAT pathway and IL-10 expression. Elucidation of the pathways of cell death and survival in EBV-infected B cells will provide opportunities for the rational design of new therapeutics to treat EBV+ B cell lymphomas.

描述（申请人提供）：EB病毒（EBV）是一种伽马疱疹病毒，与多种人类恶性肿瘤相关，包括伯基特淋巴瘤、鼻咽癌、霍奇金病、一些非霍奇金淋巴瘤以及骨髓和实体器官中的B细胞淋巴瘤接受者和艾滋病患者。在免疫抑制和免疫功能低下的个体中，普遍的观点是细胞免疫受损导致 EBV 感染的 B 细胞不受控制地扩增。然而，EBV 感染的 B 细胞的变化提供了生长和生存优势，也可能导致淋巴瘤的发生。因此，我们已经证明，从移植后淋巴增殖性疾病 (LPD) 患者建立的 EBV 感染 B 细胞系具有与细胞因子介导的细胞生长相关的 Jak/STAT 信号转导途径的组成型激活。此外，EBV 感染的 B 细胞系对 Fas/Fas 配体和 TRAIL/DR 途径诱导的细胞凋亡表现出明显的抵抗力。重要的是，潜伏 EBV 感染的建立足以赋予对先前敏感细胞的抵抗力。此外，对 Fas 诱导的细胞凋亡的抵抗与与 AP-1 激活增加相关的天然 LMP1 变体的表达相关。这项工作的长期目标是了解 EBV 如何促进 EBV 相关 B 细胞淋巴瘤的生长和存活。假设天然 LMP1 变体具有不同的调节细胞凋亡途径的能力。此外，我们假设 LMP1 与 Jak 激酶相关，并且足以激活 STAT 和产生 IL-10。具体目标 1 将确定天然 LMP1 变体免受内在和外在凋亡刺激的能力。将确定 LMP1 变体激活 NFKappaB、AP-1 和调节死亡受体近端和下游凋亡调节因子的能力。具体目标 2 将确定 LMP1 及其天然变体在 Jak/STAT 通路激活和 IL-10 表达中的作用。阐明 EBV 感染的 B 细胞的细胞死亡和存活途径将为合理设计治疗 EBV+ B 细胞淋巴瘤的新疗法提供机会。