Wnt/β-Catenin/LEF-1 Signaling in Chronic Lymphocytic Leukemia (CLL): A Target for Current and Potential Therapeutic Options
R. K. Gandhirajan,
S. J. Poll-Wolbeck,
There is a growing body of evidence that Wnt signaling, which is already known to play a critical role in various types of cancer, also has a vital function in B cell neoplasias, particularly in chronic lymphocytic leukemia (CLL). It is known that Wnt proteins are overexpressed in primary CLL cells and several physiological inhibitors are partly inactivated in this disease. Furthermore, β-catenin is upregulated upon Wnt stimulation and cooperates with the transcription factor lymphoid enhancer binding factor-1 (LEF-1). LEF-1 is excessively overexpressed in CLL cells by more than 3,000- fold compared to normal B cells. Moreover, LEF-1 could be identified as an important regulator of pathophysiologically relevant genes in CLL, and several Wnt/β-catenin signaling components substantially influence CLL cell survival. In this review we summarize the current state of knowledge about Wnt/β-catenin/LEF-1 signaling in CLL. Following a short overview of current treatment concepts in CLL, we briefly describe Wnt signaling in human cancers. We then discuss recent progress in understanding regulation of the Wnt/β-catenin/LEF-1 signaling pathway in this disease. Based on the present scientific evidence we highlight which components of this important signaling pathway could serve as therapeutic targets in CLL. We then present previous results gained from experimental approaches to target different parts of the Wnt/β-catenin/LEF-1 cascade. Together with potentially promising approaches we also critically reflect on the kind of difficulties and problems that may arise using such strategies.
Keywords: Chronic lymphocytic leukemia, leukemia, Wnt signaling, targeted therapy, IgVH mutated, IgVH unmutated, monoclonal antibodies, Purine analogues, fludarabine, pentostatin, cladribine, Fludarabine monotherapy, Rituximab, CD20, (ADCC), Alemtuzumab, CD52 antigen, (EBMT), (HSCT), complete remission, Oblimersen, planar cell polarity, (cGMP), hematopoietic stem cells, LEF/TCF, APC, GSK-3, CSKA-1, cytoplasmic protein dishevelled, SFRPs, Dickkopf related protein, E-cadherin receptor, Acute mye-loid leukemic, HEK293T cells, Wnt inhibitory factor-1, catenin, LEF-1, DNA Demethylating Agents, Ethacrynic acid, R-etodolac, (NO-NSAIDs)
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