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BCR-associated factors driving chronic lymphocytic leukemia cells proliferation ex vivo

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. Like in most mature lymphoproliferative malignancies, an antigenic stimulation is believed to drive the leukemo-genic process in chronic lymphocytic leukemia (CLL) 1-3. A restricted use of IGHV genes and the existence of ste-reotypic B cell receptor (BCR) on CLL cells 4-6 provides evidence in favor of antigenic stimulation where different microbial antigens, as well as auto-antigens, have been suspected as actors of this chronic stimulation 7. In addition , a chronic BCR self-activation has been shown in subtypes of CLL cells 8. Moreover, several signaling aberrations have been described downstream of the BCR, notably in aggressive CLL with unmutated IGHV (UM-CLL), in which the expression of ZAP70 reinforces BCR responsiveness 9-12. BCR activation, which is essential for the physiological development of lymphocytes 13 would also be indispensable for the survival and proliferation of CLL cells in vivo 2. Accordingly, withdrawal of this stimulation is believed to be responsible for the rapid spontaneous apoptosis of CLL cells ex vivo 14. The cellular consequences of this BCR activation has been extensively studied and
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Submitted on : Wednesday, September 18, 2019 - 12:33:41 AM
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Cédric Schleiss, Wassila Ilias, Ouria Tahar, Yonca Güler, Laurent Miguet, et al.. BCR-associated factors driving chronic lymphocytic leukemia cells proliferation ex vivo. Scientific Reports, Nature Publishing Group, 2019, 9 (1), ⟨10.1038/s41598-018-36853-8⟩. ⟨hal-02290791⟩

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