Pathways of Death and Survival in EBV B Cell Lymphomas

描述(申请人提供)：Epstein Barr病毒(EBV)是一种伽玛疱疹病毒，与多种人类恶性肿瘤有关，包括Burkitt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接受者和艾滋病患者的B细胞淋巴瘤。在免疫抑制和免疫受损的个体中，流行的观点是，细胞免疫受损允许EBV感染的B细胞不受控制地扩张。然而，EBV感染的B细胞中提供生长和生存优势的变化也可能有助于淋巴肿大。因此，我们已经证明，从移植后淋巴增生性疾病(LPD)患者建立的EBV感染的B细胞株具有与细胞因子介导的细胞生长相关的JAK/STAT信号转导通路的结构性激活。此外，EB病毒感染的B细胞株对通过Fas/Fas配体和TRAIL/DR途径诱导的细胞凋亡表现出明显的抵抗。重要的是，建立一种潜在的EBV感染足以使人对以前敏感的细胞产生抵抗力。此外，对Fas诱导的细胞凋亡的抵抗与与AP-1激活相关的自然LMP1变体的表达有关。这项工作的长期客观性是为了了解EBV如何促进EBV相关B细胞淋巴瘤的生长和生存。假设天然的LMP1变异体具有不同的能力来调节细胞凋亡的途径。此外，我们假设LMP1与Jak激酶相关，并足以激活STAT和产生IL-10。具体目标1将确定天然LMP1变异体保护内源性和外源性凋亡刺激的能力。LMP1变异体激活NFKappaB和AP-1并调节死亡受体凋亡的近端和下游调控因子的能力将被确定。特异性目标2将确定LMP1及其自然变异体在激活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.