title: L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo.
abstract: B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Lymph nodes (LNs) are sites of malignant proliferation and LN enlargement is associated with poor prognosis in the clinics. The LN microenvironment is believed to favor disease progression by promoting CLL cell growth and drug resistance. A better understanding of the mechanisms regulating trafficking of CLL cells to LNs is thus urgently needed. Here, we studied the first step of CLL cell migration to LNs, their interaction with high endothelial venules (HEVs), specialized blood vessels for lymphocyte extravasation in lymphoid organs. We observed that the density of HEV blood vessels was increased in CLL LNs and that CD20(+) CLL cells accumulated within HEV pockets, suggesting intense trafficking. We used intravital imaging to visualize the behavior of human CLL cells within the mouse LN microcirculation, and discovered that CLL cells bind to HEVs in vivo via a multistep adhesion cascade, which involves rolling, sticking, and crawling of the leukemic cells on the endothelium. Functional analyses revealed that the lymphocyte homing receptor L-selectin (CD62L) is the key factor controlling the binding of CLL cells to HEV walls in vivo. Interestingly, L-selectin expression was decreased on CLL cells from patients treated with idelalisib, a phosphoinositide-3-kinase δ inhibitor recently approved for CLL therapy. Interference with L-selectin-mediated trafficking in HEVs could represent a novel strategy to block dissemination of CLL cells to LNs and increase the efficacy of conventional therapy.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France; Université de Toulouse, Université Paul Sabatier, Toulouse, France;
authors.forename: Fanny
authors.initials: F
authors.lastname: Lafouresse
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France; Université de Toulouse, Université Paul Sabatier, Toulouse, France;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bellard
authors.affiliation: Centre de Recherches en Cancérologie de Toulouse, INSERM U1037, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, INSERM U563, Toulouse, France; and Laboratoire d'Anatomie et Cytologie Pathologiques, and.
authors.forename: Camille
authors.initials: C
authors.lastname: Laurent
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France; Université de Toulouse, Université Paul Sabatier, Toulouse, France;
authors.forename: Christine
authors.initials: C
authors.lastname: Moussion
authors.affiliation: Université de Toulouse, Université Paul Sabatier, Toulouse, France; Centre de Recherches en Cancérologie de Toulouse, INSERM U1037, Toulouse, France;
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Fournié
authors.affiliation: Centre de Recherches en Cancérologie de Toulouse, INSERM U1037, Toulouse, France; Service d'Hématologie, Institut Universitaire du Cancer Toulouse-Oncopôle, Toulouse, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Ysebaert
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France; Université de Toulouse, Université Paul Sabatier, Toulouse, France;
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Girard
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D000069416:Intravital Microscopy; D019041:L-Selectin / Q000502:physiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D008198:Lymph Nodes / Q000473:pathology*; D042601:Lymphatic Vessels / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D019041:L-Selectin; C552946:idelalisib