XPO1高表达在弥漫性大B细胞淋巴瘤中的临床意义及机制研究  

Clinical Significance of XPO1 High Expression in Diffuse Large B-Cell Lymphoma and Its Mechanism

作　　者：张静[1] 顾岩 管佳恒 吴雪[2] 陈宝安[1,2] ZHANG Jing;GU Yan;GUAN Jia-Heng;WU Xue;CHEN Bao-An(School of Medicine,Southeast University;Department of Hematology,Zhongda Hospital,Southeast University,Nanjing 210009,Jiangsu Province,China)

机构地区：[1]东南大学医学院,江苏南京210009 [2]东南大学附属中大医院血液科,江苏南京210009

出　　处：《中国实验血液学杂志》2025年第2期393-406,共14页Journal of Experimental Hematology

基　　金：江苏省医学重点专科(2023YXZDXK06)。

摘　　要：目的:探究核输出蛋白1(XPO1)在初发成人弥漫性大B细胞淋巴瘤(DLBCL)中的表达情况及临床意义,并进一步探索其功能机制。方法:采用免疫组化方法检测93例DLBCL和30例淋巴结反应增生患者XPO1的表达水平。构建预后风险模型以寻找DLBCL患者生存预后相关基因。通过细胞增殖、凋亡和细胞周期实验,探索XPO1抑制剂(KPT-8602)及XPO1敲降对DLBCL细胞的影响。通过分析公共数据库转录组测序结果,寻找XPO1相关差异表达基因(DEG)。结果:免疫组化结果表明,XPO1在DLBCL中的表达水平明显高于对照组(P<0.05)。与XPO1低表组相比,XPO1高表组患者的预后明显更差(P<0.05)。通过构建预后风险模型发现XPO1及核浆转运通路(NTP)中的14个基因可能是DLBCL患者的高危预后因素。此外,在两种DLBCL细胞系Farage及SU-DHL-4中,KPT-8602及XPO1敲降可以抑制DLBCL细胞的增殖、促进凋亡和阻滞细胞周期。基于公共数据库DLBCL转录组测序结果,将患者分为XPO1高表达和低表达组,分析两组的DEG,提示MYBL1可能是XPO1的下游信号分子。抑制XPO1功能或者降低XPO1表达均可以显著降低MYBL1的表达。结论:XPO1在DLBCL患者中的表达水平明显增高,且与不良预后相关。XPO1可能通过激活XPO1/MYBL1信号通路从而在DLBCL中发挥促肿瘤作用,XPO1抑制剂可能是初发DLBCL患者的一种潜在治疗选择。Objective:To explore the expression and clinical significance of XPO1 in newly diagnosed adult diffuse large B-cell lymphoma(DLBCL),and further investigate its functional mechanism.Methods:Immunohistochemical testing was conducted for XPO1 expression in 93 cases of DLBCL and 30 cases of reactive lymphoid hyperplasia.A risk model was construed to find survival related genes in DLBCL patients.Cell proliferation,apoptosis,and cell cycle assays were performed to explore the effect of XPO1 inhibitor(KPT-8602)and XPO1 knockdown.Differential expression gene(DEG)was examined based on the transcriptomes.Results:The expression of XPO1 in DLBCL patients was higher than that of the controls.Compared with XPO1 low-expression group,XPO1 high-expression group had a worse prognosis.The constructed risk model indicated that XPO1 and 14 genes in nucleocytoplasmic transport pathway(NTP)might be potential prediction marker of adverse outcome in DLBCL.Moreover,KPT-8602 as well as the XPO1 knockdown could inhibit cell proliferation,promote apoptosis,and induce cell cycle arrest in two DLBCL cell lines,Farage and SU-DHL-4.Based on the gene expression profiling in the datasets of DLBCL,patients were classified into XPO1-high and XPO1-low expression groups,and the MYBL1 was identified as the down-stream effector of XPO1.Inhibiting the function of XPO1 or reducing its expression can significantly decrease the expression of MYBL1.Conclusion:XPO1 is highly expressed in DLBCL,which is associated with poor prognosis.The oncogenic roles of the new XPO1/MYBL1 signaling are identified in DLBCL and XPO1 inhibitor may be a potential option for newly-diagnosed DLBCL patients.

关 键 词：弥漫性大B细胞淋巴瘤 XPO1 XPO1抑制剂 MYBL1 预后 

分 类 号：R733.1[医药卫生—肿瘤]