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.
©2014 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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Cell Communication
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Cell Movement / genetics
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Cell Movement / immunology
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Cell Proliferation
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Cluster Analysis
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Dendritic Cells, Follicular / immunology*
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Dendritic Cells, Follicular / metabolism
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Disease Models, Animal
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Disease Progression
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Gene Expression
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Gene Expression Profiling
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Germinal Center / immunology
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Germinal Center / metabolism
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Intracellular Signaling Peptides and Proteins / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Lymphotoxin beta Receptor / metabolism
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Mice
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Mice, Knockout
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Protein-Tyrosine Kinases / metabolism
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Receptors, CXCR5 / genetics
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Receptors, CXCR5 / metabolism
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Receptors, Complement 3b / metabolism
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Receptors, Complement 3d / metabolism
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Signal Transduction
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Spleen / immunology
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Spleen / metabolism
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Stromal Cells / metabolism
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Syk Kinase
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Tumor Microenvironment / immunology
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ZAP-70 Protein-Tyrosine Kinase / metabolism
Substances
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Intracellular Signaling Peptides and Proteins
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Lymphotoxin beta Receptor
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Receptors, CXCR5
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Receptors, Complement 3b
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Receptors, Complement 3d
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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SYK protein, human
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Syk Kinase
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Syk protein, mouse
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ZAP-70 Protein-Tyrosine Kinase