Division of Radioisotope and Tumor Pathobiology, Institute of Resource Development and Analysis, Kumamoto University, Honjo, Kumamoto, Japan; Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Honjo, Kumamoto, Japan.
Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Honjo, Kumamoto, Japan.
Neoplasia. 2024 Oct;56:101035. doi: 10.1016/j.neo.2024.101035. Epub 2024 Aug 2.
Primary effusion lymphoma (PEL) is a malignant B-cell lymphoma attributable to Kaposi sarcoma-associated herpesvirus (KSHV) infection. PEL is characterized by invasive behavior, showing recurrent effusions in body cavities. The clinical outcome and typical prognosis in patients with PEL are poor and potentially lethal. Clarification of the pathogenesis in PEL is urgently needed in order to develop novel therapies. PEL cells generally lack B-cell surface markers, and we therefore hypothesized that the B-cell transcription factor, PAX5, would be down-regulated in PEL. The expression of PAX5 is detected from the pro-B to the mature B-cell stage and is indispensable for the differentiation of B-cells. PAX5 was silenced in PEL cells via its promoter methylation. Up-regulation of PAX5 induced several genes coding for B-cell surface marker mRNA, but not protein level. PAX5 inhibited cell growth via G1 cell cycle arrest. PAX5 bound to RB and increased its protein expression. RB/E2F-regulated genes were significantly down-regulated in microarray analysis and PCR experiments. To elucidate the in vivo role of PAX5, we examined the restoration of PAX5 in a PEL mouse model. The ascites volume and organ invasions were significantly suppressed by PAX5 restoration. Reduction of PAX5 has played a crucial role in the oncogenesis of PEL, and PAX5 is a tumor suppressor in PEL. Targeting PAX5 could represent a novel therapeutic strategy for patients with PEL.
原发性渗出性淋巴瘤（PEL）是一种归因于卡波西肉瘤相关疱疹病毒（KSHV）感染的恶性 B 细胞淋巴瘤。PEL 的特征是侵袭性行为，表现为体腔反复渗出。PEL 患者的临床结局和典型预后较差，具有潜在致命性。为了开发新的治疗方法，迫切需要阐明 PEL 的发病机制。PEL 细胞通常缺乏 B 细胞表面标志物，因此我们假设 B 细胞转录因子 PAX5 在 PEL 中会下调。PAX5 的表达从前 B 细胞到成熟 B 细胞阶段都有检测到，对于 B 细胞的分化是不可或缺的。PAX5 通过其启动子甲基化在 PEL 细胞中被沉默。PAX5 的上调诱导了几个编码 B 细胞表面标志物 mRNA 的基因的上调，但不影响蛋白水平。PAX5 通过 G1 细胞周期阻滞抑制细胞生长。PAX5 与 RB 结合并增加其蛋白表达。RB/E2F 调节的基因在微阵列分析和 PCR 实验中显著下调。为了阐明 PAX5 的体内作用，我们在 PEL 小鼠模型中检查了 PAX5 的恢复情况。PAX5 的恢复显著抑制了腹水体积和器官侵袭。PAX5 的减少在 PEL 的肿瘤发生中发挥了关键作用，PAX5 是 PEL 中的肿瘤抑制因子。靶向 PAX5 可能代表 PEL 患者的一种新的治疗策略。
