Nie Danian, Xiao Xiaohui, Chen Jiaoting, Xie Shuangfeng, Xiao Jie, Yang Wenjuan, Liu Hongyun, Wang Jieyu, Ma Liping, Du Yumo, Huang Kezhi, Li Yiqing
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Exp Cell Res. 2022 Jul 15;416(2):113180. doi: 10.1016/j.yexcr.2022.113180. Epub 2022 Apr 27.
T-cell lymphoma (TCL) is a highly heterogeneous group of invasive non-Hodgkin lymphoma with adverse prognosis and limited treatment options. The relationship between TCL and Exportin-1 (XPO1), a major nuclear export receptor, has not been established yet. We here investigated the prognostic role and therapeutic implication of XPO1 in TCL. We analyzed XPO1 expression in a cohort of 69 TCL tumors and found that XPO1 was over-expressed in 76.8% of TCL and correlated with decreased progression-free survival (PFS) and overall survival (OS). In vitro treatment of TCL cell lines with KPT-8602, the second-generation selective inhibitor of nuclear export (SINE), inhibited XPO1 expression and showed significant anti-proliferative, cell-cycle arrest and pro-apoptotic efficacy. In mechanism, KPT-8602 restored the localization of cytoplasmic FOXO3A, p27, p21, IκBα and PP2A into the nucleus, leading to AKT and NF-κB deactivation. Our data demonstrate for the first time that XPO1 could be an unfavorable prognostic factor for TCL, and provide a rationale for further investigation of the efficacy of KPT-8602 in TCL patients.
T细胞淋巴瘤（TCL）是一组高度异质性的侵袭性非霍奇金淋巴瘤，预后不良且治疗选择有限。TCL与主要核输出受体输出蛋白1（XPO1）之间的关系尚未明确。我们在此研究了XPO1在TCL中的预后作用及治疗意义。我们分析了69例TCL肿瘤样本中的XPO1表达情况，发现76.8%的TCL中XPO1呈过表达，且与无进展生存期（PFS）和总生存期（OS）降低相关。用第二代核输出选择性抑制剂（SINE）KPT-8602对TCL细胞系进行体外处理，可抑制XPO1表达，并显示出显著的抗增殖、细胞周期阻滞和促凋亡功效。机制上，KPT-8602使细胞质中的FOXO3A、p27、p21、IκBα和PP2A重新定位到细胞核内，导致AKT和NF-κB失活。我们的数据首次证明XPO1可能是TCL的不良预后因素，并为进一步研究KPT-8602对TCL患者的疗效提供了理论依据。
