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- Title
BCR-associated factors driving chronic lymphocytic leukemia cells proliferation ex vivo.
- Authors
Schleiss, Cédric; Ilias, Wassila; Tahar, Ouria; Güler, Yonca; Miguet, Laurent; Mayeur-Rousse, Caroline; Mauvieux, Laurent; Fornecker, Luc-Matthieu; Toussaint, Elise; Herbrecht, Raoul; Bertrand, Frédéric; Maumy-Bertrand, Myriam; Martin, Thierry; Fournel, Sylvie; Georgel, Philippe; Bahram, Seiamak; Vallat, Laurent
- Abstract
A chronic antigenic stimulation is believed to sustain the leukemogenic development of chronic lymphocytic leukemia (CLL) and most of lymphoproliferative malignancies developed from mature B cells. Reproducing a proliferative stimulation ex vivo is critical to decipher the mechanisms of leukemogenesis in these malignancies. However, functional studies of CLL cells remains limited since current ex vivo B cell receptor (BCR) stimulation protocols are not sufficient to induce the proliferation of these cells, pointing out the need of mandatory BCR co-factors in this process. Here, we investigated benefits of several BCR co-stimulatory molecules (IL-2, IL-4, IL-15, IL-21 and CD40 ligand) in multiple culture conditions. Our results demonstrated that BCR engagement (anti-IgM ligation) concomitant to CD40 ligand, IL-4 and IL-21 stimulation allowed CLL cells proliferation ex vivo. In addition, we established a proliferative advantage for ZAP70 positive CLL cells, associated to an increased phosphorylation of ZAP70/SYK and STAT6. Moreover, the use of a tri-dimensional matrix of methylcellulose and the addition of TLR9 agonists further increased this proliferative response. This ex vivo model of BCR stimulation with T-derived cytokines is a relevant and efficient model for functional studies of CLL as well as lymphoproliferative malignancies.
- Publication
Scientific Reports, 2019, Vol 9, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-018-36853-8