Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Blood. 2011 Aug 4;118(5):1340-9. doi: 10.1182/blood-2011-02-335448. Epub 2011 Jun 9.
EBV, an oncogenic human herpesvirus, can transform primary B lymphocytes into immortalized lymphoblastoid cell lines (LCLs) through multiple regulatory mechanisms. However, the involvement of protein tyrosine kinases in the infinite proliferation of B cells is not clear. In this study, we performed kinase display assays to investigate this subject and identified a specific cellular target, Recepteur d'Origine Nantais (RON) tyrosine kinase, expressed in LCLs but not in primary B cells. Furthermore, we found that latent membrane protein 1 (LMP1), an important EBV oncogenic protein, enhanced RON expression through its C-terminal activation region-1 (CTAR1) by promoting NF-κB binding to the RON promoter. RON knockdown decreased the proliferation of LCLs, and transfection with RON compensated for the growth inhibition caused by knockdown of LMP1. Immunohistochemical analysis revealed a correlation between LMP1 and RON expression in biopsies from posttransplantation lymphoproliferative disorder (PTLD), suggesting that LMP1-induced RON expression not only is essential for the growth of LCLs but also may contribute to the pathogenesis of EBV-associated PTLD. Our study is the first to reveal the impact of RON on the proliferation of transformed B cells and to suggest that RON may be a novel therapeutic target for EBV-associated lymphoproliferative diseases.
EBV，一种致癌的人类疱疹病毒，可通过多种调节机制将原代 B 淋巴细胞转化为永生化淋巴母细胞系（LCL）。然而，蛋白酪氨酸激酶在 B 细胞的无限增殖中的参与尚不清楚。在本研究中，我们进行了激酶展示测定来研究这个问题，并鉴定了一个特定的细胞靶标，RON 酪氨酸激酶，在 LCL 中表达，但不在原代 B 细胞中表达。此外，我们发现潜伏膜蛋白 1（LMP1），一种重要的 EBV 致癌蛋白，通过其 C 端激活区-1（CTAR1）促进 NF-κB 与 RON 启动子结合，增强 RON 表达。RON 敲低降低了 LCL 的增殖，而 LMP1 敲低引起的生长抑制可以通过转染 RON 得到补偿。免疫组织化学分析显示移植后淋巴组织增生性疾病（PTLD）活检中 LMP1 和 RON 表达之间存在相关性，提示 LMP1 诱导的 RON 表达不仅对 LCL 的生长至关重要，而且可能有助于 EBV 相关 PTLD 的发病机制。本研究首次揭示了 RON 对转化 B 细胞增殖的影响，并提示 RON 可能是 EBV 相关淋巴增生性疾病的一个新的治疗靶点。
