title: Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia.
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.
authors.affiliation: INSERM U978, Bobigny, France.|Université Paris 13, Sorbonne Paris Cité, Labex "Inflamex", Bobigny, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Saint-Georges
authors.affiliation: INSERM U978, Bobigny, France.|Université Paris 13, Sorbonne Paris Cité, Labex "Inflamex", Bobigny, France.
authors.forename: Maude
authors.initials: M
authors.lastname: Quettier
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Unité de Recherche Clinique, Bobigny, France.
authors.forename: Marouane
authors.initials: M
authors.lastname: Bouyaba
authors.affiliation: INSERM U978, Bobigny, France.|Université Paris 13, Sorbonne Paris Cité, Labex "Inflamex", Bobigny, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Le Coquil
authors.affiliation: INSERM U978, Bobigny, France.|Université Paris 13, Sorbonne Paris Cité, Labex "Inflamex", Bobigny, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Laurienté
authors.affiliation: INSERM U978, Bobigny, France.|Université Paris 13, Sorbonne Paris Cité, Labex "Inflamex", Bobigny, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Guittat
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Unité de Recherche Clinique, Bobigny, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lévy
authors.affiliation: INSERM U978, Bobigny, France.|Université Paris 13, Sorbonne Paris Cité, Labex "Inflamex", Bobigny, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Service d'Hématologie Biologique, Bobigny, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Ajchenbaum-Cymbalista
authors.affiliation: INSERM U978, Bobigny, France.|Université Paris 13, Sorbonne Paris Cité, Labex "Inflamex", Bobigny, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Varin-Blank
authors.affiliation: INSERM U978, Bobigny, France.|Université Paris 13, Sorbonne Paris Cité, Labex "Inflamex", Bobigny, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Le Roy
authors.affiliation: INSERM U978, Bobigny, France.|Université Paris 13, Sorbonne Paris Cité, Labex "Inflamex", Bobigny, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Ledoux
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000072281:Lymphadenopathy / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; C089212:protein kinase D; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D011493:Protein Kinase C
keywords: B-cell receptor; CLL; CXCR4/CXCR5; lymphadenopathy; protein kinase D