Wu Wei, Zhu Huayuan, Fu Yuan, Shen Wenyi, Miao Kourong, Hong Min, Xu Wei, Fan Lei, Young Ken H, Liu Peng, Li Jianyong
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Oncotarget. 2016 Apr 19;7(16):21631-43. doi: 10.18632/oncotarget.7795.
Aberrant activation of lymphoid enhancer-binding factor-1 (LEF1) has been identified in several cancers, including chronic lymphocytic leukemia (CLL). As a key transcription factor of the Wnt/β-catenin pathway, LEF1 helps to regulate important genes involved in tumor cell death mechanisms. In this study, we determined LEF1 gene expression levels in CLL (n = 197) and monoclonal B-cell lymphocytosis (MBL) (n = 6) patients through real-time RT-PCR. LEF1 was significantly up-regulated in both MBL and CLL patients compared with normal B cells. Treatment-free survival (TFS) time and overall survival (OS) time were much longer in CLL patients with low LEF1 expression than in those with high LEF1 levels. Furthermore, Wnt inhibitor ethacrynic acid (EA) induced both apoptosis and necroptosis in primary CLL cells. EA also enhanced the cytotoxicity of both fludarabine and cyclophosphamide against CLL cells in vitro. Finally, we demonstrated that EA functions by inhibiting the recruitment of LEF1 to DNA promoters and restoring cylindromatosis (CYLD) expression in CLL cells. Our results showed, for the first time, that high LEF1 expression is associated with poor survival for CLL patients. Combined with other chemotherapeutic drugs, EA may be a promising therapeutic agent for CLL.
在包括慢性淋巴细胞白血病（CLL）在内的多种癌症中，已发现淋巴样增强子结合因子1（LEF1）的异常激活。作为Wnt/β-连环蛋白通路的关键转录因子，LEF1有助于调节参与肿瘤细胞死亡机制的重要基因。在本研究中，我们通过实时逆转录聚合酶链反应（RT-PCR）测定了CLL患者（n = 197）和单克隆B细胞淋巴细胞增多症（MBL）患者（n = 6）的LEF1基因表达水平。与正常B细胞相比，MBL和CLL患者的LEF1均显著上调。LEF1低表达的CLL患者的无治疗生存期（TFS）和总生存期（OS）比LEF1高表达的患者长得多。此外，Wnt抑制剂依他尼酸（EA）可诱导原发性CLL细胞凋亡和坏死性凋亡。EA还增强了氟达拉滨和环磷酰胺在体外对CLL细胞的细胞毒性。最后，我们证明EA通过抑制LEF1募集到DNA启动子并恢复CLL细胞中的圆柱瘤蛋白（CYLD）表达发挥作用。我们的结果首次表明，LEF1高表达与CLL患者的不良生存相关。与其他化疗药物联合使用时，EA可能是一种有前景的CLL治疗药物。
