High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation.
In lymphatic tissues, chronic lymphocytic leukemia (CLL) cells are interspersed with CD68(+) nurselike cells (NLCs), T cells, and other stromal cells that constitute the leukemia microenvironment. However, the mechanism regulating colocalization of CLL and these accessory cells are largely unknown. To dissect the molecular cross talk between CLL and NLCs, we profiled the gene expression of CD19-purified CLL cells before and after coculture with NLCs. NLC coculture induced high-level expression of B-cell maturation antigen and 2 chemoattractants (CCL3, CCL4) by CLL cells. CCL3/CCL4 induction in NLC cocultures correlated with ZAP-70 expression by CLL cells. High CCL3/CCL4 protein levels were found in CLL cocultures with NLCs, and CCL3/CCL4 induction was abrogated by R406, a Syk inhibitor, suggesting that NLCs 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 2 T-cell chemokines in response to NLC coculture and BCR stimulation. Through these chemokines, CLL cells can recruit accessory cells and thereby actively create a supportive microenvironment.
Burger
Jan A
JA
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX 77230-1402, USA. jaburger@mdanderson.org
Quiroga
Maite P
MP
Hartmann
Elena
E
Bürkle
Andrea
A
Wierda
William G
WG
Keating
Michael J
MJ
Rosenwald
Andreas
A
D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D054405:Chemokine CCL3 / Q000235:genetics* / Q000378:metabolism; D054407:Chemokine CCL4 / Q000235:genetics* / Q000378:metabolism; D018920:Coculture Techniques / Q000379:methods; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism
D000888:Antibodies, Anti-Idiotypic; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D017077:Culture Media, Conditioned; C044203:anti-IgM; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr