title: Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B-cell activation and proliferation.
abstract: In human chronic lymphocytic leukemia (CLL) pathogenesis, B-cell antigen receptor signaling seems important for leukemia B-cell ontogeny, whereas the microenvironment influences B-cell activation, tumor cell lodging, and provision of antigenic stimuli. Using the murine Eμ-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell-like leukemia cell trafficking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin-β-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin-β-receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli.
  
  
  CONCLUSIONS
  CLL and other indolent lymphoma are not curable and usually relapse after treatment, a process in which the tumor microenvironment plays a pivotal role. We dissect the consecutive steps of CXCR5-dependent tumor cell lodging and LTβR-dependent stroma-leukemia cell interaction; moreover, we provide therapeutic solutions to interfere with this reciprocal tumor-stroma cross-talk.
authors.affiliation: Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Heinig
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Gätjen
authors.affiliation: Department of Physics, Philipps-University Marburg, Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Grau
authors.affiliation: Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Stache
authors.affiliation: Department of Pathology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Anagnostopoulos
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gerlach
authors.affiliation: Deutsches Rheumaforschungszentrum, DRFZ, Berlin, Germany.
authors.forename: Raluca A
authors.initials: RA
authors.lastname: Niesner
authors.affiliation: Deutsches Rheumaforschungszentrum, DRFZ, Berlin, Germany. Confocal and 2-Photon Microscopy Core Facility, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Cseresnyes
authors.affiliation: Deutsches Rheumaforschungszentrum, DRFZ, Berlin, Germany. Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Anja E
authors.initials: AE
authors.lastname: Hauser
authors.affiliation: Department of Physics, Philipps-University Marburg, Marburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lenz
authors.affiliation: Institute for Immunology, University Regensburg, Regensburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hehlgans
authors.affiliation: Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Westermann
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany. Department of Hematology, Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.affiliation: Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany. Department of Hematology, Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany. uhoepken@mdc-berlin.de arehm@mdc-berlin.de.
authors.forename: Armin
authors.initials: A
authors.lastname: Rehm
authors.affiliation: Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany. uhoepken@mdc-berlin.de arehm@mdc-berlin.de.
authors.forename: Uta E
authors.initials: UE
authors.lastname: Höpken
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002450:Cell Communication; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D016000:Cluster Analysis; D020566:Dendritic Cells, Follicular / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D020869:Gene Expression Profiling; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000235:genetics / Q000378:metabolism; D017463:Receptors, Complement 3b / Q000378:metabolism; D017464:Receptors, Complement 3d / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D000072377:Syk Kinase; D059016:Tumor Microenvironment / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D053259:Lymphotoxin beta Receptor; D054380:Receptors, CXCR5; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase