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Blood, 26 March 2009, Vol. 113, No. 13, pp. 3050-3058.
Prepublished online as a Blood First Edition Paper on December 12, 2008; DOI 10.1182/blood-2008-07-170415.
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Submitted July 25, 2008
Accepted November 22, 2008
High-level expression of the T cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell co-cultures and after BCR stimulation
Jan A. Burger*, Maite P. Quiroga, Elena Hartmann, Andrea Burkle, William G Wierda, Michael J. Keating, and Andreas Rosenwald
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
Institute of Pathology, University of Wurzburg, Wurzburg, Germany
Department of Medicine, Division of Hematology/Oncology, Freiburg University Hospital, Freiburg, Germany
* Corresponding author; email: jaburger{at}mdanderson.org.
In lymphatic tissues, chronic lymphocytic leukemia (CLL) cells are interspersed with CD68+ nurselike cells (NLC), T cells, and other stromal cells that constitute the leukemia microenvironment. However, the mechanism regulating co-localization of CLL and these accessory cells are largely unknown. To dissect the molecular cross-talk between CLL and NLC, we profiled the gene expression of CD19-purified CLL cells before and after co-culture with NLC. NLC co-culture induced high-level expression of B cell maturation antigen (BCMA) and two chemoattractants (CCL3, CCL4) by CLL cells. CCL3/CCL4 induction in NLC co-cultures correlated with ZAP-70 expression by CLL cells. High CCL3/CCL4 protein levels were found in CLL co-cultures with NLC, and CCL3/CCL4 induction was abrogated by R406, a Syk inhibitor, suggesting that NLC induce these chemokines via B cell receptor (BCR) activation. BCR triggering also caused robust CCL3/CCL4 protein secretion by CLL cells. High CCL3 and CCL4 plasma levels in CLL patients suggest that this pathway plays a role in vivo. These studies reveal a novel mechanism of cross-talk between CLL cells and their microenvironment, namely the secretion of two T cell chemokines in response to NLC co-culture and BCR stimulation. Through these chemokines, CLL cells can recruit accessory cells, and thereby actively create a supportive microenvironment.
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