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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Impact Journals LLC
2016
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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. |
format | Online Article Text |
id | pubmed-5173040 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
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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