Role of Epstein-Barr Virus in Burkitt Lymphoma

描述（由申请人提供）：本基金支持的长期目标是确定eb病毒（EBV）在伯基特淋巴瘤（BL）中的作用，伯基特淋巴瘤是一种发生在不同地理区域的b细胞肿瘤，也与HIV感染和艾滋病导致的免疫抑制有关。这项资助的基本假设是EBV直接导致了BL，尽管在肿瘤细胞中缺乏已知的病毒转化基因的表达。观察结果支持了这一点，即BL细胞系Akata的致瘤潜力依赖于EBV感染和至少两种病毒基因产物EBV小rna EBER-1和EBER-2。然而，相对于EBV感染整体而言，EBER rna对致瘤潜能的贡献是部分的，这表明在感染BL细胞期间表达的其他病毒基因是重要的。这项工作的直接目标是确定EBER rna和其他EBV基因产物对BL细胞致瘤潜能和淋巴瘤发生本身的机制贡献。提出了三个具体目标。在目标1中，我们将确定EBER rna的细胞靶标，并确定其调控机制。我们将讨论先前实验观察提出的两种可能的EBER功能机制。首先，EBER RNA通过直接RNA （RNA与细胞基因RNA的相互作用）在转录后基因沉默中起作用。第二，基于已知的eber与细胞翻译机制组成部分的相互作用，eber调节特定细胞mrna的翻译。在Aim 2下，我们将定义EBV BamHI右向转录本（BARTs）编码的蛋白质对BL细胞致瘤潜力的贡献，特别是这些蛋白质中是否有任何蛋白质负责EBV赋予BL细胞的增强存活，这归因于在生长限制条件下病毒强制下调c-MYC原癌蛋白。在Aim 3中，我们将使用BL小鼠模型，Emu-myc转基因小鼠，评估BL细胞系中表达的EBV基因对实际淋巴瘤发生的重要性，其中c-myc原癌基因的表达与BL中一样，在B淋巴细胞中组成性过表达。具体来说，我们将在这些小鼠的B细胞内表达EBV基因，以确定这是否会加速c- myc诱导的淋巴瘤发生，如果是这样，我们将确定其对淋巴瘤的贡献的遗传和生化基础。

DESCRIPTION (provided by applicant): The long-term objective of the work supported by this grant is to define the role of Epstein-Barr virus (EBV) in Burkitt lymphoma (BL), a B-cell tumor that occurs in geographically distinct regions, and which is also associated with immunosuppression as a consequence of HIV infection and AIDS. The underlying hypothesis of this grant is that EBV contributes directly to BL, despite lack of expression of the known viral transforming genes within the tumor cells. This is supported by the observation that the tumorigenic potential of the BL cell line Akata is dependent on EBV infection and at least two viral gene products the EBV small RNAs EBER-1 and EBER-2. The contribution of the EBER RNAs to tumorigenic potential, however, is partial relative to that conferred by EBV infection as a whole, indicating that additional viral genes expressed during infection of BL cells are important. The immediate goals of the proposed work are to define the mechanistic contributions of the EBER RNAs and other EBV gene products to the tumorigenic potential of BL cells and to lymphomagenesis itself. Three specific aims are proposed. Under Aim 1, we will identify the cellular targets of the EBER RNAs and define the mechanisms through which they are regulated. We will address two potential mechanisms of EBER function that are suggested by previous experimental observations. The first is that the EBER RNAs function in posttranscriptional gene silencing through direct RNA:RNA interactions with cellular gene RNAs. The second, based on known interactions of the EBERs with components of the cellular translational machinery, is that the EBERs regulate translation of specific cellular mRNAs. Under Aim 2, we will define the contributions of proteins encoded by the EBV BamHI rightward transcripts (BARTs) to BL-cell tumorigenic potential, and in particular whether any of these proteins are responsible for the enhanced survival conferred upon BL cells by EBV that is attributed to viral-enforced down-regulation of the c-MYC proto-oncoprotein under growth-limiting conditions. Under Aim 3, we will assess the importance of EBV genes expressed in BL cell lines to actual lymphomagenesis using the murine model of BL, the Emu-myc transgenic mouse, in which expression of the c-myc proto-oncogene, as in BL, is constitutively overexpressed in B lymphocytes. Specifically, we will express the EBV genes within the B cells of these mice to determine whether this accelerates c-Myc-induced lymphomagenesis, and if so, we will identify the genetic and biochemical basis for this contribution to lymphoma.