Restoring PU.1 induces apoptosis and modulates viral transactivation via interferon-stimulated genes in primary effusion lymphoma
Restoring PU.1 induces apoptosis and modulates viral transactivation via interferon-stimulated genes in primary effusion lymphoma
复制标题
在原发性渗出性淋巴瘤中恢复 PU.1 可诱导细胞凋亡并通过干扰素刺激基因调节病毒反式激活
作者：
Goto H;Kariya R;Kudo E;Okuno Y;Ueda K;Katano H;Okada S
原发性渗出性淋巴瘤（PEL）是与卡波西肉瘤相关的疱疹病毒/人疱疹病毒-8相关的侵袭性B细胞淋巴瘤亚群，标准治疗难治，并且表现出较差的存活率。虽然PU。1在PEL中下调，其减少的潜在作用仍有待阐明。在这项研究中，我们分析了PU的DNA甲基化。1顺式调控元件及其对PU修复的影响。1对PEL细胞。PU的mRNA水平。1在PEL细胞中表达下调。PU的甲基化启动子和增强子区域。1个基因。PU的恢复导致细胞生长抑制和凋亡。1例。微阵列分析显示，干扰素刺激的基因（ISGs），包括促凋亡ISGs的强烈增加后，在BCBL-1细胞的诱导PU。1.报告基因分析表明，PU. 1反式激活促凋亡ISG启动子，如XAF 1、OAS 1和TRAIL启动子。PU处的突变。1结合序列抑制其反式激活。我们证实了PU的结合。1与XAF 1、OAS 1和TRAIL启动子的结合。PU. 1通过诱导IRF 7抑制ORF 57的活化。PU的再引入。1减少了PEL异种移植模型小鼠腹水的形成和远处器官的淋巴瘤细胞浸润。总的来说，PU。1在PEL的肿瘤抑制中具有作用，并且其下调与PEL的发展相关。恢复PU。1与去甲基化剂联合应用可能是治疗PEL的一种新方法。
Primary effusion lymphoma (PEL), which is an aggressive subgroup of B-cell lymphoma associated with Kaposi sarcoma-associated herpes virus/human herpes virus-8, is refractory to the standard treatment, and exhibits a poor survival. Although PU. 1 is downregulated in PEL, the potential role of its reduction remains to be elucidated. In this investigation, we analyzed the DNA methylation of PU. 1 cis-regulatory elements in PEL and the effect of restoring PU. 1 on PEL cells. The mRNA level of PU. 1 was downregulated in PEL cells. The methylated promoter and enhancer regions of the PU. 1 gene were detected in PEL cells. Suppression of cell growth and apoptosis were caused by the restoration of PU. 1 in PEL cells. A microarray analysis revealed that interferon-stimulated genes (ISGs) including pro-apoptotic ISGs were strongly increased in BCBL-1 cells after the induction of PU. 1. Reporter assays showed that PU. 1 transactivated pro-apoptotic ISG promoters, such as the XAF1, OAS1 and TRAIL promoters. Mutations at the PU. 1 binding sequences suppressed its transactivation. We confirmed the binding of PU. 1 to the XAF1, OAS1 and TRAIL promoters in a chromatin immunoprecipitation assay. PU. 1 suppressed ORF57 activation by inducing IRF7. The reinduction of PU. 1 reduced formation of ascites and lymphoma cell infiltration of distant organs in PEL xenograft model mice. Collectively, PU. 1 has a role in tumor suppression in PEL and its down-regulation is associated with PEL development. Restoring PU. 1 with demethylation agents may be a novel therapeutic approach for PEL.