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

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Blood First Edition Paper, prepublished online December 12, 2008; DOI

10.1182/blood-2008-07-170415.

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, Burkle, G

Wierda, J. Keating, and s Rosenwald

Department of Leukemia, The University of Texas MD 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@... .

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.