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Cancer Discov. 2014 Dec;4(12):1448-65. doi: 10.1158/2159-8290.CD-14-0096. Epub 2014 Sep 24.

Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B-cell activation and proliferation.

Author information

1
Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.
2
Department of Hematology, Oncology and Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.
3
Department of Physics, Philipps-University Marburg, Marburg, Germany.
4
Department of Pathology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
5
Deutsches Rheumaforschungszentrum, DRFZ, Berlin, Germany.
6
Deutsches Rheumaforschungszentrum, DRFZ, Berlin, Germany. Confocal and 2-Photon Microscopy Core Facility, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.
7
Deutsches Rheumaforschungszentrum, DRFZ, Berlin, Germany. Charité-Universitätsmedizin Berlin, Berlin, Germany.
8
Institute for Immunology, University Regensburg, Regensburg, Germany.
9
Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
10
Department of Hematology, Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
11
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.
12
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.
13
Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany. uhoepken@mdc-berlin.de arehm@mdc-berlin.de.

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.

SIGNIFICANCE:

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.

PMID:
25252690
DOI:
10.1158/2159-8290.CD-14-0096
[Indexed for MEDLINE]
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