Factors involved in CLL pathogenesis and cell survival are disrupted by differentiation of CLL B-cells into antibody-secreting cells
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Hussein Ghamlouch1,2,5, Walaa Darwiche3, Ahmed Hodroge1, Hakim Ouled-Haddou1, Sébastien Dupont1,5, Amrathlal Rabbind Singh1, Caroline Guignant1,2, Stéphanie Trudel1,4, Bruno Royer1,5, Brigitte Gubler1,2,4,*, Jean-Pierre Marolleau1,5,*
1EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France
2Department of Immunology, Amiens University Medical Center, Amiens, France
3PériTox, Périnatalité & Risques Toxiques, UMR-I 01 Unité mixte INERIS, Amiens, France
4Department of Molecular Oncobiology, Amiens University Medical Center, Amiens, France
5Department of Clinical Hematology and Cell Therapy, Amiens University Medical Center, Amiens, France
*These authors have contributed equally to this work
Hussein Ghamlouch, e-mail: firstname.lastname@example.org
Jean-Pierre Marolleau, e-mail: email@example.com
Keywords: chronic lymphocytic leukemia, B-cell differentiation, apoptosis, LEF1, ROR1
Received: March 10, 2015 Accepted: April 28, 2015 Published: May 11, 2015
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.
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