Human B-lymphocytes express 5-lipoxygenase (5-LOX) and 5-LOX activating protein (FLAP) and can convert arachidonic acid to leukotriene B₄. Mantle cell lymphoma (MCL) cells contain similar amounts of 5-LOX as human neutrophils but the function and mechanism of activation of 5-LOX in MCL cells, and in normal B-lymphocytes, are unclear. Here we show that the intrinsic 5-LOX pathway in the MCL cell line JeKo-1 has an essential role in migration and adherence of the cells, which are important pathophysiological characteristics of B-cell lymphoma. Incubation of JeKo-1 with the FLAP inhibitor GSK2190915 or the 5-LOX inhibitor zileuton, at a concentration below 1 μM, prior to stimulation with the chemotactic agent CXCL12, led to a significant reduction of migration. CRISPR/Cas9 mediated deletion of ALOX5 gene in JeKo-1 cells also led to a significantly decreased migration of the cells. Furthermore, 5-LOX and FLAP inhibitors markedly decreased the adherence of JeKo-1 cells to stromal cells. In comparison, these drugs had a similar effect on adherence of JeKo-1 cells as the Bruton tyrosine kinase inhibitor ibrutinib, which has a proven anti-tumour effect. These results indicate that inhibition of 5-LOX may be a novel treatment for MCL and certain other B-cell lymphomas.

人B淋巴细胞表达5-脂氧合酶(5-LOX)和5-LOX激活蛋​​白(FLAP)，并且可以将花生四烯酸转化为白三烯B ₄ 。套细胞淋巴瘤 (MCL) 细胞含有与人类中性粒细胞相似数量的 5-LOX，但 MCL 细胞和正常 B 淋巴细胞中 5-LOX 的功能和激活机制尚不清楚。在这里，我们证明 MCL 细胞系 JeKo-1 中的内在 5-LOX 通路在细胞的迁移和粘附中发挥重要作用，这是 B 细胞淋巴瘤的重要病理生理学特征。在用趋化剂 CXCL12 刺激之前，将 JeKo-1 与浓度低于 1 μM 的 FLAP 抑制剂 GSK2190915 或 5-LOX 抑制剂齐留通一起孵育，可导致迁移显着减少。 JeKo-1 细胞中 CRISPR/Cas9 介导的ALOX5基因缺失也导致细胞迁移显着减少。此外，5-LOX 和 FLAP 抑制剂显着降低 JeKo-1 细胞对基质细胞的粘附。相比之下，这些药物对 JeKo-1 细胞粘附的影响与布鲁顿酪氨酸激酶抑制剂依鲁替尼相似，后者已被证明具有抗肿瘤作用。这些结果表明，抑制 5-LOX 可能是治疗 MCL 和某些其他 B 细胞淋巴瘤的新方法。