title: Differentiation of chronic lymphocytic leukemia B cells into immunoglobulin secreting cells decreases LEF-1 expression.
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.
authors: Department of Immunology, Mayo Graduate School, College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors: Albert
authors: A
authors: Gutierrez
authors: Bonnie K
authors: BK
authors: Arendt
authors: Renee C
authors: RC
authors: Tschumper
authors: Neil E
authors: NE
authors: Kay
authors: Clive S
authors: CS
authors: Zent
authors: Diane F
authors: DF
authors: Jelinek
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: C513533:CpG ODN 2006; D016207:Cytokines; D007147:Immunoglobulin Light Chains; D051821:Lymphoid Enhancer-Binding Factor 1; D009838:Oligodeoxyribonucleotides; D012097:Repressor Proteins; D051153:Wnt Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1