title: Factors involved in CLL pathogenesis and cell survival are disrupted by differentiation of CLL B-cells into antibody-secreting cells.
abstract: Recent research has shown that chronic lymphocytic leukemia (CLL) B-cells display a strong tendency to differentiate into antibody-secreting cells (ASCs) and thus may be amenable to differentiation therapy. However, the effect of this differentiation on factors associated with CLL pathogenesis has not been reported. In the present study, purified CLL B-cells were stimulated to differentiate into ASCs by phorbol myristate acetate or CpG oligodeoxynucleotide, in combination with CD40 ligand and cytokines in a two-step, seven-day culture system. We investigated (i) changes in the immunophenotypic, molecular, functional, morphological features associated with terminal differentiation into ASCs, (ii) the expression of factors involved in CLL pathogenesis, and (iii) the expression of pro- and anti-apoptotic proteins in the differentiated cells. Our results show that differentiated CLL B-cells are able to display the transcriptional program of ASCs. Differentiation leads to depletion of the malignant program and deregulation of the apoptosis/survival balance. Analysis of apoptosis and the cell cycle showed that differentiation is associated with low cell viability and a low rate of cell cycle entry. Our findings shed new light on the potential for differentiation therapy as a part of treatment strategies for CLL.
authors.affiliation: EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.|Department of Immunology, Amiens University Medical Center, Amiens, France.|Department of Clinical Hematology and Cell Therapy, Amiens University Medical Center, Amiens, France.
authors.forename: Hussein
authors.initials: H
authors.lastname: Ghamlouch
authors.affiliation: PériTox, Périnatalité & Risques Toxiques, UMR-I 01 Unité mixte INERIS, Amiens, France.
authors.forename: Walaa
authors.initials: W
authors.lastname: Darwiche
authors.affiliation: EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hodroge
authors.affiliation: EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Hakim
authors.initials: H
authors.lastname: Ouled-Haddou
authors.affiliation: EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.|Department of Clinical Hematology and Cell Therapy, Amiens University Medical Center, Amiens, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dupont
authors.affiliation: EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Amrathlal Rabbind
authors.initials: AR
authors.lastname: Singh
authors.affiliation: EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.|Department of Immunology, Amiens University Medical Center, Amiens, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Guignant
authors.affiliation: EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.|Department of Molecular Oncobiology, Amiens University Medical Center, Amiens, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Trudel
authors.affiliation: EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.|Department of Clinical Hematology and Cell Therapy, Amiens University Medical Center, Amiens, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Royer
authors.affiliation: EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.|Department of Immunology, Amiens University Medical Center, Amiens, France.|Department of Molecular Oncobiology, Amiens University Medical Center, Amiens, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gubler
authors.affiliation: EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.|Department of Clinical Hematology and Cell Therapy, Amiens University Medical Center, Amiens, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marolleau
mesh_terms: D000921:Antibody-Producing Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000494:pharmacology; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D007132:Immunoglobulin Isotypes / Q000276:immunology / Q000378:metabolism; D016130:Immunophenotyping; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: C107489:BIRC5 protein, human; C408982:CPG-oligonucleotide; D016207:Cytokines; D007132:Immunoglobulin Isotypes; D051034:Inhibitor of Apoptosis Proteins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D009838:Oligodeoxyribonucleotides; D000077022:Survivin; D023201:CD40 Ligand; D013755:Tetradecanoylphorbol Acetate
keywords: B-cell differentiation; LEF1; ROR1; apoptosis; chronic lymphocytic leukemia