High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid
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Wei Wu1, Huayuan Zhu1, Yuan Fu1, Wenyi Shen1, Kourong Miao1, Min Hong1, Wei Xu1, Lei Fan1, Ken H. Young2, Peng Liu1,3 and Jianyong Li1
1 Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China
2 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3 Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China
Jianyong Li, email:
Peng Liu, email:
Keywords: chronic lymphocytic leukemia, LEF1, CYLD, necroptosis, ethacrynic acid
Received: July 31, 2015 Accepted: February 05, 2016 Published: February 29, 2016
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.
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