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Abstract
Lymphocyte enhancer binding factor 1 (LEF-1) plays a crucial role in B lineage development and is only expressed in B cell precursors as B cell differentiation into mature B and plasma cells silences its expression. Chronic lymphocytic leukemia (CLL) cells aberrantly express LEF-1 and its expression is required for cellular survival. We hypothesized that modification of the differentiation status of CLL cells would result in loss of LEF-1 expression and eliminate the survival advantage provided by its aberrant expression. In this study, we first established a methodology that induces CLL cells to differentiate into immunoglobulin (Ig) secreting cells (ISC) using the TLR9 agonist, CpG, together with cytokines (CpG/c). CpG/c stimulation resulted in dramatic CLL cell phenotypic and morphologic changes, expression of cytoplasmic Ig, 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 data support the notion that CLL can differentiate into ISC and that this triggers decreased leukemic cell survival secondary to the down regulation of LEF-1 and decreased Wnt pathway activation.
Highlights
Chronic lymphocytic leukemia (CLL) is a clonal expansion of neoplastic mature B lymphocytes and is the most prevalent lymphoid malignancy in the United States
Because lymphoid enhancer binding factor-1 (LEF-1) is a central mediator of the wingless-type MMTV integration site (Wnt) pathway and because differentiation of CLL B cells into ISC resulted in decreased expression of LEF-1, we evaluated the level of Wnt pathway activation in these cells
We identified a pathogenic role for LEF-1 and the Wnt pathway in CLL B cells
Summary
Chronic lymphocytic leukemia (CLL) is a clonal expansion of neoplastic mature B lymphocytes and is the most prevalent lymphoid malignancy in the United States. CLL is effectively treated with chemo-immunotherapy CLL remains an incurable malignancy with conventional management. To better understand this disease, state of the art genomic methodologies have been employed[1,2,3,4] to identify genes involved in disease pathogenesis. We hypothesized that differentiation of leukemic B cells into immunoglobulin (Ig) secreting cells (ISC) would result in loss of LEF-1 expression and decreased leukemic cell survival
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