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Leukotriene A₄ Hydrolase Expression in PEL Cells Is Regulated at the Transcriptional Level and Leads to Increased Leukotriene B₄ Production¹

Meztli Arguello^*,, Suzanne Paz^*,, Eduardo Hernandez^*, Catherine Corriveau-Bourque^*,, Lama M. Fawaz^,, John Hiscott^2,*,, and Rongtuan Lin^2,*,

^* Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada; Department of Microbiology and Immunology, Department of Medicine, and Meakins-Christie Laboratories, McGill University, Montreal, Canada

Primary effusion lymphoma (PEL) is a herpesvirus-8-associated lymphoproliferative disease characterized by migration of tumor cells to serous body cavities. PEL cells originate from postgerminal center B cells and share a remarkable alteration in B cell transcription factor expression and/or activation with classical Hodgkin’s disease cells. Comparative analysis of gene expression by cDNA microarray of BCBL-1 cells (PEL), L-428 (classical Hodgkin’s disease), and BJAB cells revealed a subset of genes that were differentially expressed in BCBL-1 cells. Among these, four genes involved in cell migration and chemotaxis were strongly up-regulated in PEL cells: leukotriene A₄ (LTA₄) hydrolase (LTA₄H), IL-16, thrombospondin-1 (TSP-1), and selectin-P ligand (PSGL-1). Up-regulation of LTA₄H was investigated at the transcriptional level. Full-length LTA₄H promoter exhibited 50% higher activity in BCBL-1 cells than in BJAB or L-428 cells. Deletion analysis of the LTA₄H promoter revealed a positive cis-regulatory element active only in BCBL-1 cells in the promoter proximal region located between –76 and –40 bp. Formation of a specific DNA-protein complex in this region was confirmed by EMSA. Coculture of ionophore-stimulated primary neutrophils with BCBL-1 cells leads to an increased production of LTB₄ compared with coculture with BJAB and L-428 cells as measured by enzyme immunoassay, demonstrating the functional significance of LTA₄H up-regulation.

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