Targeting B Cell MicroRNA in Post-Transplant EBV-Associated B Cell Lymphoma

 描述（由申请人提供）：爱泼斯坦巴尔病毒（EBV）是一种γ疱疹病毒，已感染>90%的人群。EBV感染通常是无症状的，并通过强大的T细胞介导的免疫反应控制。然而，EBV也可引起传染性单核细胞增多症，并与多种淋巴和上皮恶性肿瘤有关。免疫抑制的移植受体和免疫功能低下的个体，如AIDS患者或老年人，发生EBV+ B细胞淋巴瘤的风险增加。虽然免疫力受损明显有助于这些人群中EBV+ B细胞淋巴瘤的出现，但对EBV驱动肿瘤细胞增殖的机制知之甚少。我们实验室最近的研究表明，EBV感染显著改变了受感染B细胞内的细胞microRNA（miRNA）谱。miRNA是一个重要的非编码小RNA网络，在转录后水平控制基因表达，从而影响细胞功能。在我们观察到的由EBV调节的miRNA中，预测一个子集靶向人IL-10的3'非翻译区（UTR），IL-10是移植受体中EBV+ B细胞淋巴瘤的已知自分泌生长因子。我们已经证明，这些miRNA之一，miR-194，在EBV感染B细胞时被抑制。我们进一步表明miR-194与IL- 10的3 'UTR结合，并且在来自患有移植后淋巴增生性疾病（PTLD）的移植受者的EBV+ B细胞系中miR-194的过表达显著抑制IL-10的产生。在这个项目中，我们测试的假设，EBV劫持宿主B细胞的miRNA，以促进细胞增殖，通过组成性生产的IL-10，这是一个新的，但靶向，发病机制的EBV+ B细胞淋巴瘤。这一假设将在两个具体目标中得到检验。首先，我们将确定EBV是否通过调节宿主细胞miRNA诱导人IL-10。其次，我们将确定靶向EBV调节宿主细胞miRNA是否可以在体内防止EBV+ B细胞淋巴瘤的增殖。拟议的研究具有创新性和潜在的高影响力，因为它们将确定和定义EBV+ B细胞淋巴瘤病毒诱导发病机制的新模式，并评估这是否构成潜在的治疗靶点。此外，它们将提供关于IL-10表达调控的基础知识，这可能对其他IL-10产生细胞具有重要意义。

 DESCRIPTION (provided by applicant): Epstein Barr Virus (EBV) is a gamma herpes virus that has infected >90% of the human population. EBV infection is usually asymptomatic and is controlled by a robust T cell-mediated immune response. However, EBV can also cause infectious mononucleosis and is linked to a variety of lymphoid and epithelial malignancies. Immunosuppressed transplant recipients and individuals who are immunocompromised such as AIDS patients or the elderly, are at increased risk of developing EBV+ B cell lymphomas. While impaired immunity clearly contributes to the emergence of EBV+ B cell lymphomas in these populations, the mechanisms by which EBV drives tumor cell proliferation are poorly understood. Recent studies in our laboratory indicate that EBV infection significantly alters the cellular microRNA (miRNA) profile within infected B cells. miRNA constitute an important network of small, non-coding RNA that control gene expression at the post-transcriptional level and thereby impacts cellular function. Of the miRNA that we observed are modulated by EBV, a subset is predicted to target the 3' untranslated region (UTR) of human IL-10, a known autocrine growth factor for EBV+ B cell lymphomas in transplant recipients. We have shown that one of these miRNA, miR-194, is suppressed upon EBV infection of B cells. We further show that miR-194 binds to the 3'UTR of IL- 10 and that overexpression of miR-194 in EBV+ B cell lines from transplant recipients with post-transplant lymphoproliferative disorder (PTLD) significantly inhibits IL-10 production. In this project we test the hypothesis that EBV hijacks host B cell miRNA to promote cell proliferation through constitutive production of IL-10 and that this is a novel, but targetable, mechanism of pathogenesis in EBV+ B cell lymphomas. This hypothesis will be tested in two specific aims. First, we will establish whether EBV induces human IL-10 through modulation of host cell miRNA. Second, we will determine whether targeting EBV regulation of host cell miRNA can prevent proliferation of EBV+ B cell lymphomas in vivo. The proposed studies are innovative and of potentially high impact because they will identify and define a novel mode of virally-induced pathogenesis for EBV+ B cell lymphomas and evaluate whether this constitutes a potential therapeutic target. Moreover, they will provide fundamental knowledge on regulation of IL-10 expression that could have important implications for other IL-10 producing cells.