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 Blood, 1 November 2007, Vol. 110, No. 9, pp. 3316-3325.
Prepublished online as a Blood First Edition Paper on July 25, 2007; DOI 10.1182/blood-2007-05-089409.

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NEOPLASIA

Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia

Andrea Bürkle1, Matthias Niedermeier2, Annette Schmitt-Gräff3, William G. Wierda2, Michael J. Keating2, and Jan A. Burger1,2

1 Department of Medicine, Division of Hematology/Oncology, Freiburg University Hospital, Freiburg, Germany; 2 Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and 3 Department of Pathology, Freiburg University Hospital, Freiburg, Germany

CXCL13 is a homeostatic chemokine for lymphocyte homing and positioning within follicles of secondary lymphoid tissues, acting through its cognate receptor, CXCR5. Moreover, the CXCR5-CXCL13 axis plays a unique role in trafficking and homing of B1 cells. Here, we report that chronic lymphocytic leukemia (CLL) B cells express high levels of functional CXCR5. CXCR5 expression levels were similar on CLL B cells and normal CD5+ B cells, and higher compared with normal CD5– B cells, follicular B-helper T cells (TFH cells), or neoplastic B cells from other B-cell neoplasias. Stimulation of CLL cells with CXCL13 induces actin polymerization, CXCR5 endocytosis, chemotaxis, and prolonged activation of p44/42 mitogen-activated protein kinases. Anti-CXCR5 antibodies, pertussis toxin, and wortmannin inhibited chemotaxis to CXCL13, demonstrating the importance of Gi proteins and PI3 kinases for CXCR5 signaling. Moreover, CLL patients had significantly higher CXCL13 serum levels than volunteers, and CXCL13 levels correlated with ß2 microglobulin. We detected CXCL13 mRNA expression by nurselike cells, and high levels of CXCL13 protein in supernatants of CLL nurselike cell cultures. By immunohistochemistry, we detected CXCL13+ expression by CD68+ macrophages in situ within CLL lymph nodes. These data suggest that CXCR5 plays a role in CLL cell positioning and cognate interactions between CLL and CXCL13-secreting CD68+ accessory cells in lymphoid tissues.


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