title: High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid.
abstract: 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.
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: Huayuan
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: Kourong
authors.initials: K
authors.lastname: Miao
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Hong
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
authors.affiliation: 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 Hematology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000074749:Deubiquitinating Enzyme CYLD / Q000235:genetics / Q000378:metabolism; D004976:Ethacrynic Acid / Q000494:pharmacology*; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009336:Necrosis / Q000235:genetics / Q000517:prevention & control; D011379:Prognosis; D034622:RNA Interference; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D000074749:Deubiquitinating Enzyme CYLD; D004976:Ethacrynic Acid
keywords: CYLD; LEF1; chronic lymphocytic leukemia; ethacrynic acid; necroptosis