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

Abstract

UNLABELLED:

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.

• Authors: Kristina Heinig, Marcel Gätjen, Michael Grau, Vanessa Stache, Ioannis Anagnostopoulos, Kerstin Gerlach, Raluca A Niesner, Zoltan Cseresnyes, Anja E Hauser, Peter Lenz, Thomas Hehlgans, Robert Brink, Jörg Westermann, Bernd Dörken, Martin Lipp, Georg Lenz, Armin Rehm, Uta E Höpken
• Journal: Cancer discovery (Cancer Discov) Vol. 4 Issue 12 Pg. 1448-65 (Dec 2014) ISSN: 2159-8290 [Electronic] United States
• PMID: 25252690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Intracellular Signaling Peptides and Proteins
• Lymphotoxin beta Receptor
• Receptors, CXCR5
• Receptors, Complement 3b
• Receptors, Complement 3d
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• SYK protein, human
• Syk Kinase
• Syk protein, mouse
• ZAP-70 Protein-Tyrosine Kinase

Topics

• Agammaglobulinaemia Tyrosine Kinase
• Animals
• Cell Communication
• Cell Movement (genetics, immunology)
• Cell Proliferation
• Cluster Analysis
• Dendritic Cells, Follicular (immunology, metabolism)
• Disease Models, Animal
• Disease Progression
• Gene Expression
• Gene Expression Profiling
• Germinal Center (immunology, metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics, immunology, metabolism, pathology)
• Lymphotoxin beta Receptor (metabolism)
• Mice
• Mice, Knockout
• Protein-Tyrosine Kinases (metabolism)
• Receptors, CXCR5 (genetics, metabolism)
• Receptors, Complement 3b (metabolism)
• Receptors, Complement 3d (metabolism)
• Signal Transduction
• Spleen (immunology, metabolism)
• Stromal Cells (metabolism)
• Syk Kinase
• Tumor Microenvironment (immunology)
• ZAP-70 Protein-Tyrosine Kinase (metabolism)