Pathways of Death and Survival in EBV B Cell Lymphomas

描述（由申请人提供）：eb病毒（EBV）是一种伽玛疱疹病毒，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和骨髓和实体器官受体及艾滋病患者的B细胞淋巴瘤。在免疫抑制和免疫功能低下的个体中，普遍的观点是受损的细胞免疫允许ebv感染的B细胞不受控制地扩增。然而，eb病毒感染的B细胞中提供生长和生存优势的改变也可能导致淋巴瘤的发生。因此，我们已经证明，从移植后淋巴细胞增生性疾病（LPD）患者身上建立的ebv感染的B细胞系具有与细胞因子介导的细胞生长相关的Jak/STAT信号转导通路的组成性激活。此外，ebv感染的B细胞系对Fas/Fas配体和TRAIL/DR途径诱导的凋亡表现出明显的抗性。重要的是，潜伏性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AP-1激活增加相关的天然LMP1变异的表达有关。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。假设是天然LMP1变体具有调节细胞凋亡途径的不同能力。此外，我们假设LMP1与Jak激酶相关，足以激活STAT和产生IL-10。特异性目的1将确定天然LMP1变异对内源性和外源性凋亡刺激的保护能力。LMP1变异体激活NFKappaB、AP-1和调节死亡受体近端和下游细胞凋亡调节因子的能力将被确定。特异性Aim 2将确定LMP1及其自然变体在激活Jak/STAT通路和IL-10表达中的作用。阐明EBV感染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。

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.