Identification of a naturally occurring model for EBV-associated lymphomagenesis

描述（由申请人提供）：人类慢性感染典型γ -1疱疹病毒eb病毒（EBV）通常是无症状的，然而，感染与人类淋巴和上皮恶性肿瘤有关。EBV在淋巴瘤发生中的作用一直难以阐明，部分原因是影响病毒发病机制的并发遗传和环境因素，如自发性染色体易位，在研究环境中难以准确建模。家犬的自发性淋巴瘤包括大量异质性的恶性肿瘤，包括弥漫性大B细胞淋巴瘤（DLBCL）和伯基特样淋巴瘤，它们表现出与人类NHL亚型相似的遗传和细胞遗传学变化。此外，狗的品种与淋巴瘤易感性之间的强烈关联表明，遗传因素在决定淋巴瘤易感性方面起着关键作用。我们的初步数据支持并扩展了最近发表的研究结果，即家养狗携带ebv样γ疱疹病毒，这可能导致该物种的自发性淋巴瘤。综上所述，这些发现表明狗的淋巴瘤形成可能具有病毒病因，并概括了与人类淋巴瘤病毒发病机制相关的遗传和表观遗传事件的复杂相互作用。在这个探索性的提议中，我们将探讨宠物狗感染具有致癌潜力的γ疱疹病毒的中心假设。我们将进行一项前瞻性、纵向血清流行病学研究，以评估金毛犬病毒感染与B细胞淋巴瘤发展之间的关系。金毛猎犬在遗传上易患淋巴瘤，发病率特别高（每8只狗中就有1只患病）。该品种内有限的遗传异质性提供了一个独特的机会，以确定在该物种中易发生病毒相关淋巴瘤的病毒因子和基因，我们相信这将与促进人类ebv相关淋巴瘤发生的机制直接相关。此外，我们的目标是利用我们对犬临床组织标本和自发性B细胞淋巴瘤犬的血清/血浆样本的无限获取，分离并进一步表征犬ebv样疱疹病毒。我们预计我们的结果将成为未来R01的基础，旨在研究这种假定的ebv相关疱疹病毒在狗的淋巴瘤发生中的作用，并将狗建立为临床相关的、自发的模型来研究病毒相关的淋巴瘤发生。如果我们的假设是正确的，这里提出的研究结果将对人类健康产生重大影响，将狗确定为临床相关的、自发的、大型动物模型，用于确定影响病毒转化的因素，并在临床前环境中测试和推进病毒靶向治疗。

DESCRIPTION (provided by applicant): Chronic infection with the prototypic gamma-1 herpesvirus, Epstein-Barr Virus (EBV) in humans is usually asymptomatic, however, infection has been associated with lymphoid and epithelial malignancies in humans. The role of EBV in lymphomagenesis has been difficult to elucidate in part because concurrent genetic and environmental factors that influence viral pathogenesis such as spontaneous chromosomal translocations are difficult to accurately model in the research setting. Spontaneous lymphoma in the domestic dog comprises a large heterogeneous group of malignancies including Diffuse Large B Cell Lymphoma (DLBCL) and Burkitt-like lymphoma, that displaying similar genetic and cytogenetic changes to NHL subtypes in humans. Furthermore, the strong association between dog breed and predisposition to lymphoma indicates that genetic factors play a key role in determining susceptibility to lymphoma. Our preliminary data support and expand recent published findings that domestic dogs harbor an EBV-like gammaherpesvirus and that this may contribute to spontaneous lymphoma in this species. Taken together, these findings suggest that lymphomagenesis in dogs may have a viral etiology and recapitulate the complex interplay of genetic and epigenetic events associated with the viral pathogenesis of lymphoma in humans. In this exploratory proposal, we will explore the central hypothesis that pet dogs are infected with a gammaherpesvirus that has oncogenic potential. We will perform a prospective, longitudinal sero- epidemiological study to evaluate the association between viral infection and the development of B cell lymphoma in the Golden Retriever dog. Golden Retrievers are genetically predisposed to lymphoma and have an exceptionally high incidence of disease (incidence of 1 in 8 dogs). The limited genetic heterogeneity within the breed provides a unique opportunity to identify viral factors and genes that predispose to virus-associated lymphomagenesis in this species and we believe that this will have direct relevance to mechanisms promoting EBV-associated lymphomagenesis in humans. In addition, we aim to take advantage of our unlimited access to canine clinical tissue specimens and serum/plasma samples from dogs with spontaneous B cell lymphoma, to isolate and further characterize the canine EBV-like herpesvirus. We anticipate that our results will form the basis of a future R01 designed to investigate the role of this putative EBV-related herpesvirus in lymphomagenesis in dogs and establish the dog as a clinically relevant, spontaneous model to study viral- associated lymphomagenesis. If our hypothesis is correct, the results from the studies proposed here will have a significant impact on human health, identifying the dog as a clinically relevant, spontaneous, large animal model in which to identify factors influencing viral transformation and to test and advance virus targeted therapies in a pre-clinical setting.