Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia
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Stéphane Saint-Georges1,2, Maude Quettier1,2, Marouane Bouyaba3, Stéphanie Le Coquil1,2, Vanessa Laurienté1,2, Lionel Guittat1,2, Vincent Lévy3, Florence Ajchenbaum-Cymbalista1,2,4, Nadine Varin-Blank1,2, Christine Le Roy1,2,* and Dominique Ledoux1,2,*
1 INSERM U978, Bobigny, France
2 Université Paris 13, Sorbonne Paris Cité, Labex “Inflamex”, Bobigny, France
3 Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Unité de Recherche Clinique, Bobigny, France
4 Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Service d’Hématologie Biologique, Bobigny, France
* These authors are co-senior authors
Christine Le Roy, email:
Nadine Varin-Blank, email:
Keywords: CLL, lymphadenopathy, B-cell receptor, CXCR4/CXCR5, protein kinase D
Received: December 23, 2015 Accepted: April 16, 2016 Published: April 26, 2016
In Chronic Lymphocytic Leukemia (CLL), infiltration of lymph nodes by leukemic cells is observed in patients with progressive disease and adverse outcome. We have previously demonstrated that B-cell receptor (BCR) engagement resulted in CXCR4 down-regulation in CLL cells, correlating with a shorter progression-free survival in patients. In this study, we show a simultaneous down-regulation of CXCR4, CXCR5 and CD62L upon BCR triggering. While concomitant CXCR4 and CXCR5 down-regulation involves PKDs, CD62L release relies on PKC activation. BCR engagement induces PI3K-δ-dependent phosphorylation of PKD2 and 3, which in turn phosphorylate CXCR4 Ser324/325. Moreover, upon BCR triggering, PKD phosphorylation levels correlate with the extent of membrane CXCR4 decrease. Inhibition of PKD activity restores membrane expression of CXCR4 and migration towards CXCL12 in BCR-responsive cells in vitro. In terms of pathophysiology, BCR-dependent CXCR4 down-regulation is observed in leukemic cells from patients with enlarged lymph nodes, irrespective of their IGHV mutational status. Taken together, our results demonstrate that PKD-mediated CXCR4 internalization induced by BCR engagement in B-CLL is associated with lymph node enlargement and suggest PKD as a potential druggable target for CLL therapeutics.
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