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.
Highlights
Chronic lymphocytic leukemia (CLL) is a B-cell hematological malignancy characterized by the clonal expansion and accumulation of morphologically mature B-lymphocytes in peripheral blood, bone marrow, and secondary lymphoid tissues
These results indicated a role for Lymphoid enhancer binding factor-1 (LEF1) in CLL leukemogenesis, so we wished to further investigate the potential prognostic effect of LEF1 expression in CLL patients
We have identified the overexpression of LEF1 in CD5+ B cells from monoclonal B-cell lymphocytosis (MBL) and CLL patients compared to those from healthy donors
Summary
Chronic lymphocytic leukemia (CLL) is a B-cell hematological malignancy characterized by the clonal expansion and accumulation of morphologically mature B-lymphocytes in peripheral blood, bone marrow, and secondary lymphoid tissues. The progressive accumulation of leukemic cells is mostly ascribed to extended cellular survival rather than excessive cellular proliferation [1]. Investigation of aberrantly activated genes with prognostic relevance in CLL may help to identify those patients with a poorer prognosis and to develop novel therapeutic targets for CLL. LEF1 plays a critical role in normal human hematopoiesis, especially in the development of B- and T-lymphocytes [4,5]. Aberrant expression of LEF1 has been found in several hematological malignancies [6,7,8,9,10,11,12] in human. The prognostic significance of LEF1 expression has not been thoroughly clarified in CLL
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