Redondo-Muñoz Javier, José Terol María, García-Marco José A, García-Pardo Angeles
Departamento de Fisiopatología Celular y Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid.
Blood. 2008 Jan 1;111(1):383-6. doi: 10.1182/blood-2007-08-107300. Epub 2007 Sep 21.
B-cell chronic lymphocytic leukemia (B-CLL) progression is frequently accompanied by clinical lymphadenopathy, and the CCL21 chemokine may play an important role in this process. Indeed, CCR7 (the CCL21 receptor), as well as matrix metalloproteinase-9 (MMP-9), are overexpressed in infiltrating B-CLL cells. We have studied whether MMP-9 is regulated by CCL21 and participates in CCL21-dependent migration. CCL21 significantly increased B-CLL MMP-9 production, measured by gelatin zymography. This was inhibited by blocking extracellular signal-regulated kinase-1/2 (ERK1/2) activity or by cell transfection with CCR7-siRNA. Accordingly, CCL21/CCR7 interaction activated the ERK1/2/c-Fos pathway and increased MMP-9 mRNA. CCL21-driven B-CLL cell migration through Matrigel or human umbilical vein endothelial cells (HUVEC) was blocked by anti-CCR7 antibodies, CCR7-siRNA transfection, or the ERK1/2 inhibitor U0126, as well as by anti-MMP-9 antibodies or tissue inhibitor of metalloproteinase 1 (TIMP-1). These results strongly suggest that MMP-9 is involved in B-CLL nodal infiltration and expand the roles of MMP-9 and CCR7 in B-CLL progression. Both molecules could thus constitute therapeutic targets for this disease.
B细胞慢性淋巴细胞白血病（B-CLL）的进展常伴有临床淋巴结病，趋化因子CCL21可能在此过程中起重要作用。实际上，CCR7（CCL21受体）以及基质金属蛋白酶-9（MMP-9）在浸润性B-CLL细胞中过表达。我们研究了MMP-9是否受CCL21调控并参与CCL21依赖的迁移。通过明胶酶谱法检测，CCL21显著增加B-CLL中MMP-9的产生。阻断细胞外信号调节激酶-1/2（ERK1/2）活性或用CCR7-siRNA转染细胞可抑制此现象。相应地，CCL21/CCR7相互作用激活ERK1/2/c-Fos途径并增加MMP-9 mRNA。CCL21驱动B-CLL细胞通过基质胶或人脐静脉内皮细胞（HUVEC）的迁移被抗CCR7抗体、CCR7-siRNA转染、ERK1/2抑制剂U0126以及抗MMP-9抗体或金属蛋白酶组织抑制剂1（TIMP-1）阻断了。这些结果强烈表明MMP - 9参与B-CLL淋巴结浸润，并扩展了MMP-9和CCR7在B-CLL进展中的作用。因此，这两种分子都可能成为该疾病的治疗靶点。
