title: The arachidonic acid-LTB4-BLT2 pathway enhances human B-CLL aggressiveness.
abstract: Deregulation of the oxidative cascade of poly-unsaturated fatty acids (PUFAs) has been associated with several cancers, including chronic lymphocytic leukemia (B-CLL). Leukotriene B4 (LTB4), a metabolite of arachidonic acid (AA), is produced by B-CLL and contributes to their survival. The aim of the present study was to analyze the activity of the oxidative cascade of PUFAs in B-CLL. Purified B cells from patients and normal B CD5 positive cells were subjected to flow cytometry, Western-blot and RT-qPCR analyses. LTB4 plasma and intracellular concentrations were determined by ELISA. Our results showed that aggressive B-CLL tumor cells, i.e. cells with an annual proliferation index above 2, over-expressed calcium-dependent and calcium-independent phospholipases A2 (cPLA2-alpha and iPLA2-beta, respectively), 5-lipoxygenase (5LOX) and leukotriene A4 hydroxylase (LTA4H). Intracellular LTB4 levels were lower in the most aggressive cells than in cells with a smaller proliferation index, despite equivalent plasma levels, and lower expression of cytochrome P450 4F3A (CYP4F3A), one major enzyme involved in LTB4 inactivation. Since BLT2, a LTB4 membrane receptor was also more often expressed on aggressive tumor cells, and since a BLT2 inhibitor significantly impaired B-CLL viability in vitro, we propose that LTB4 was efficiently trapped onto BLT2 present on aggressive tumors, thereby eliciting an autocrine response. Taken together our results demonstrate a major deregulation of the pathway leading to LTB4 synthesis and degradation in B-CLL cells, and provide a framework for understanding how these modifications promote cell survival and proliferation, especially in the most aggressive BCLL.
authors: Laboratoire de thérapie cellulaire et d'immunobiologie des cancers, CHU, Hôpital Morvan, 5, avenue Foch, 29200 Brest, France. Electronic address: nathalie.guriec@univ-brest.fr.
authors: Nathalie
authors: N
authors: Guriec
authors: UMR INSERM 1078, SFR ScInBioS, CHU, Faculté de médecine, 22 avenue C. Desmoulins, 29200 Brest, France.
authors: Catherine
authors: C
authors: Le Jossic-Corcos
authors: UMR INSERM 1078, SFR ScInBioS, CHU, Faculté de médecine, 22 avenue C. Desmoulins, 29200 Brest, France.
authors: Brigitte
authors: B
authors: Simon
authors: Service d'hématologie clinique, CHU, Hôpital Morvan, 5, avenue Foch, 29200 Brest, France.
authors: Jean-Christophe
authors: JC
authors: Ianotto
authors: Service d'hématologie clinique, CHU, Hôpital Morvan, 5, avenue Foch, 29200 Brest, France.
authors: Adrian
authors: A
authors: Tempescul
authors: UMR INSERM 1078, SFR ScInBioS, CHU, Faculté de médecine, 22 avenue C. Desmoulins, 29200 Brest, France.
authors: Yvonne
authors: Y
authors: Dréano
authors: UMR INSERM 1078, SFR ScInBioS, CHU, Faculté de médecine, 22 avenue C. Desmoulins, 29200 Brest, France.
authors: Jean-Pierre
authors: JP
authors: Salaün
authors: Laboratoire de thérapie cellulaire et d'immunobiologie des cancers, CHU, Hôpital Morvan, 5, avenue Foch, 29200 Brest, France; Service d'hématologie clinique, CHU, Hôpital Morvan, 5, avenue Foch, 29200 Brest, France.
authors: Christian
authors: C
authors: Berthou
authors: UMR INSERM 1078, SFR ScInBioS, CHU, Faculté de médecine, 22 avenue C. Desmoulins, 29200 Brest, France.
authors: Laurent
authors: L
authors: Corcos
keywords: B-CLL; BLT2; Disease progression; LTB4; PPAR