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

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...

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Autores principales: Saint-Georges, Stéphane, Quettier, Maude, Bouyaba, Marouane, Le Coquil, Stéphanie, Laurienté, Vanessa, Guittat, Lionel, Lévy, Vincent, Ajchenbaum-Cymbalista, Florence, Varin-Blank, Nadine, Le Roy, Christine, Ledoux, Dominique
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173040/
https://www.ncbi.nlm.nih.gov/pubmed/27127886
http://dx.doi.org/10.18632/oncotarget.9031
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author Saint-Georges, Stéphane
Quettier, Maude
Bouyaba, Marouane
Le Coquil, Stéphanie
Laurienté, Vanessa
Guittat, Lionel
Lévy, Vincent
Ajchenbaum-Cymbalista, Florence
Varin-Blank, Nadine
Le Roy, Christine
Ledoux, Dominique
author_facet Saint-Georges, Stéphane
Quettier, Maude
Bouyaba, Marouane
Le Coquil, Stéphanie
Laurienté, Vanessa
Guittat, Lionel
Lévy, Vincent
Ajchenbaum-Cymbalista, Florence
Varin-Blank, Nadine
Le Roy, Christine
Ledoux, Dominique
author_sort Saint-Georges, Stéphane
collection PubMed
description 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 Ser(324/325). 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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spelling pubmed-51730402016-12-23 Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia Saint-Georges, Stéphane Quettier, Maude Bouyaba, Marouane Le Coquil, Stéphanie Laurienté, Vanessa Guittat, Lionel Lévy, Vincent Ajchenbaum-Cymbalista, Florence Varin-Blank, Nadine Le Roy, Christine Ledoux, Dominique Oncotarget Research Paper 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 Ser(324/325). 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. Impact Journals LLC 2016-04-26 /pmc/articles/PMC5173040/ /pubmed/27127886 http://dx.doi.org/10.18632/oncotarget.9031 Text en Copyright: © 2016 Saint-Georges et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Saint-Georges, Stéphane
Quettier, Maude
Bouyaba, Marouane
Le Coquil, Stéphanie
Laurienté, Vanessa
Guittat, Lionel
Lévy, Vincent
Ajchenbaum-Cymbalista, Florence
Varin-Blank, Nadine
Le Roy, Christine
Ledoux, Dominique
Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia
title Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia
title_full Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia
title_fullStr Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia
title_full_unstemmed Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia
title_short Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia
title_sort protein kinase d-dependent cxcr4 down-regulation upon bcr triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173040/
https://www.ncbi.nlm.nih.gov/pubmed/27127886
http://dx.doi.org/10.18632/oncotarget.9031
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