Autocrine Function of Cysteinyl-Leukotrienes and Their Receptor CysLT1 in Chronic Lymphocytic Leukemia (B-CLL).

Abstract 2325

Poster Board II-302

Leukocytes, including B cells, represent the physiological source of lipid mediators of the cysteinyl-leukotriene family. In malignant B cells, particularly in B-CLL, even higher levels of enzymes involved in leukotriene biosynthesis have been detected. The major receptor for cysteinyl-leukotrienes, CysLT1, mediates pleiotropic effects on cell migration, proliferation and survival. In the present study, we found that CysLT1 was consistently overepressed in B-CLL with mRNA levels 2-4-fold greater than in normal B cells, as detected by real-time PCR. The CysLT1 receptor was highly active in CLL cell lines (MEC-1, EHEB) and primary B-CLL cells, as demonstrated by ligand-induced intracellular calcium fluxes and actin polymerization (measured by flow cytometry), chemotaxis (Boyden chamber assay), and MAP-kinase/Erk1/2 phosphorylation (analyzed with Western blot). The effects were completely blocked by the CysLT1 antagonist MK-571. Upregulation of both the CysLT1 receptor and enzymes of leukotriene biosynthesis, in conjunction with the CysLT1-mediated activation of the MAP-kinase/Erk signaling pathway, suggest an autocrine loop contributing to cell survival. Indeed, incubation of CLL cells in serum-free medium with the CysLT1 antagonist reduced their viability in a dose-dependent manner by up to 70% (24 h) and 80% (48 h) compared to cells which were cultured without the antagonist. Our results provide evidence that cysteinyl-leukotrienes and their receptor regulate survival of CLL cells in an autocrine fashion, and imply a therapeutic potential of CysLT1 receptor antagonists, currently used in asthma therapy, also in the treatment of B-CLL.