Pathways of Death and Survival in EBV B Cell Lymphomas

描述（由申请方提供）：爱泼斯坦巴尔病毒（EBV）是一种γ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、某些非霍奇金淋巴瘤和骨髓和实体器官接受者及艾滋病患者中的B细胞淋巴瘤。在免疫抑制和免疫受损的个体中，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，EBV感染的B细胞的改变提供了生长和存活优势，也可能有助于淋巴瘤的发生。因此，我们已经证明，从患有移植后淋巴增生性疾病（LPD）的患者建立的EBV感染的B细胞系具有Jak/STAT信号转导途径的组成性激活，该信号转导途径与精氨酸介导的细胞生长相关。此外，EBV感染的B细胞系显示出对通过Fas/Fas配体和TRAIL/DR途径诱导凋亡的显著抗性。重要的是，潜伏性EBV感染的建立足以赋予对先前敏感的细胞的抗性。此外，对Fas诱导的细胞凋亡的抗性与AP-1激活增加相关的天然LMP 1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。假设是天然LMP 1变体具有调节细胞凋亡途径的不同能力。此外，我们假设LMP 1与Jak激酶相关，足以激活STAT和产生IL-10。特异性目的1将决定天然LMP 1变体保护免受内在和外在凋亡刺激的能力。将测定LMP 1变体激活NF κ B、AP-1和调节凋亡的死亡受体近端和下游调节物的能力。具体目标2将确定LMP 1及其天然变体在Jak/STAT途径和IL-10表达的激活中的作用。阐明EBV感染的B细胞中细胞死亡和存活的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.