Oncotarget

Research Papers:

Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia

Stéphane Saint-Georges, Maude Quettier, Marouane Bouyaba, Stéphanie Le Coquil, Vanessa Laurienté, Lionel Guittat, Vincent Lévy, Florence Ajchenbaum-Cymbalista, Nadine Varin-Blank, Christine Le Roy and Dominique Ledoux _

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Oncotarget. 2016; 7:41031-41046. https://doi.org/10.18632/oncotarget.9031

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Abstract

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

Correspondence to:

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

Abstract

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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