%0 Journal Article %T Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia %+ Adaptateurs de signalisation en hématologie (ASIH) %+ Adaptateurs de signalisation en hématologie (ASIH) %+ Université Paris 13 (UP13) %+ Hôpital Avicenne [AP-HP] %+ Centre d'Investigations Cliniques 9504 %A Saint-Georges, Stéphane %A Quettier, Maude %A Bouyaba, Marouane %A Le Coquil, Stéphanie %A Laurienté, Vanessa %A Guittat, Lionel %A Levy, Vincent %A Ajchenbaum-Cymbalista, Florence %A Varin-Blank, Nadine %A Le Roy, Christine %A Ledoux, Dominique %< avec comité de lecture %@ 1949-2553 %J Oncotarget %I Impact journals %V 7 %N 27 %8 2016-07-05 %D 2016 %R 10.18632/oncotarget.9031 %K CLL %K lymphadenopathy %K B-cell receptor %K CXCR4/CXCR5 %K protein kinase D %Z Life Sciences [q-bio]Journal articles %X 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. %G English %L hal-02060827 %U https://sorbonne-paris-nord.hal.science/hal-02060827 %~ UNIV-PARIS7 %~ UNIV-PARIS13 %~ APHP %~ USPC %~ ASIH %~ SORBONNE-PARIS-NORD %~ UNIV-PARIS %~ SIMHEL