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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1274-1279.
Prepublished online as a Blood First Edition Paper on September 28, 2004; DOI 10.1182/blood-2004-07-2546.
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NEOPLASIA
Leukotriene B4 plays a pivotal role in CD40-dependent activation of chronic B lymphocytic leukemia cells
Gudmundur Runarsson,
Anquan Liu,
Yilmaz Mahshid,
Stina Feltenmark,
Annika Pettersson,
Eva Klein,
Magnus Björkholm, and
Hans-Erik Claesson
From the Departments of Medicine and Medical Biochemistry and Biophysics, and the Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; and the Division of Molecular Neurobiology, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
Biosynthesis of leukotrienes (LTs) occurs in human myeloid cells and B lymphocytes. However, the function of leukotrienes in B lymphocytes is unclear. Here, we report that B-cell chronic lymphocytic leukemia (B-CLL) cells produce leukotriene B4, and that specific leukotriene biosynthesis inhibitors counteracted CD40-dependent activation of B-CLL cells. Studies on the expression of the high-affinity receptor for LTB4 (BLT1) by flow cytometry analysis showed that the receptor was expressed, to a varying degree, in all investigated B-CLL clones. At a concentration of 100 nM, the drugs BWA4C (a specific 5-lipoxygenase inhibitor) and MK-886 (a specific 5-lipoxygenase activating protein inhibitor) markedly inhibited CD40-induced DNA synthesis (45% and 38%, respectively) and CD40-induced expression of CD23, CD54, and CD150. Addition of exogenous LTB4 (150 nM) almost completely reversed the effect of the inhibitors on DNA synthesis and antigen expression. Taken together, the results of the present study suggest that leukotriene biosynthesis inhibitors may have a therapeutic role in B-CLL.
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