differentiation of chronic lymphocytic leukemia b cells into immunoglobulin secreting cells decreases lef-1 expression慢性淋巴细胞白血病b细胞的分化成免疫球蛋白分泌细胞减少lef-1表达式.pdfVIP

Differentiation of Chronic Lymphocytic Leukemia B Cells into Immunoglobulin Secreting Cells Decreases LEF-1 Expression 1 1 1 2 2 Albert Gutierrez Jr. , Bonnie K. Arendt , Renee C. Tschumper , Neil E. Kay , Clive S. Zent , Diane F. Jelinek1* 1 Department of Immunology, Mayo Graduate School, College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America, 2 Department of Internal Medicine, Mayo Graduate School, College of Medicine, Rochester, Mayo Clinic, Minnesota, United States of America 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 supp