| The canonical Wnt signaling pathway is pathogenic in a variety of cancers. Expression of the Wnt pathway transcription factor and target gene lymphoid enhancer binding factor 1 (LEF-1) in chronic lymphocytic leukemia (CLL) suggested that the Wnt signaling pathway has a role in the biology of CLL. In this study, we identified aberrant regulation of Wnt pathway target genes, ligands, and signaling members in CLL cells. Using the TCF/LEF dual luciferase reporter assay, we demonstrated constitutive Wnt pathway activation in CLL, while the pathway was inactive in normal peripheral B cells. Importantly, LEF-1 knockdown decreased CLL B cell survival. We also identified LEF-1 expression in CD19+/CD5+ cells obtained from patients with monoclonal B cell lymphocytosis (MBL), suggesting a role for LEF-1 early in CLL leukemogenesis. Further, because LEF-1 expression is extinguished during normal B cell development, we hypothesized that the differentiation of CLL cells would result in loss of LEF-1 expression. We established a methodology that induces CLL cells to differentiate into immunoglobulin (Ig) secreting cells (ISC) using CpG together with cytokines (CpG/c). CpG/c stimulation induced CLL cell morphologic changes and secretion of light chain restricted Ig. CpG/c stimulation also resulted in decreased CLL cell LEF-1 expression and increased Blimp-1 expression, which is crucial for plasma cell differentiation. Further, Wnt pathway activation and cellular survival were impaired in differentiated CLL cells compared to undifferentiated CLL cells. These studies have identified the constitutive activation and pro-survival function of LEF-1 and the Wnt pathway in CLL and uncovered a possible role for differentiation therapy in CLL. |
