Ticchioni M, Essafi M, Jeandel P Y, Davi F, Cassuto J P, Deckert M, Bernard A
Département d'Immunologie, Hôpital de l'Archet, Université de Nice-Sophia Antipolis, Nice, France.
Oncogene. 2007 Nov 1;26(50):7081-91. doi: 10.1038/sj.onc.1210519. Epub 2007 May 14.
B-chronic lymphocytic leukemia (B-CLL) cell is characterized by the accumulation of long-lived CD5+ B lymphocytes, whose survival in vivo is in part dependent on exogenous factors such as cytokines and/or extracellular matrix proteins. Homeostatic chemokines are critical mediators of lymphoid cell trafficking. However, how they function in cell signaling and survival remains ill-defined. In this study, we have investigated the role of the homeostatic chemokines, CXCL12, CCL21, CCL19 and CXCL13, in B-CLL cell survival. Using primary leukemic cells isolated from 26 patients, we observed that each chemokine enhances cell survival. Chemokines induced the phosphorylation of ERK1/2 and p90RSK, and of Akt and its effectors GSK3 and FOXO3a. Consistently, inhibitors against mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase inhibited chemokine-induced survival. Moreover, using a constitutively active mutated form of FOXO3a or siRNAs against FOXO3a in transfection experiments performed in primary B-CLL cells, we directly demonstrated the critical role of FOXO3a in both spontaneous and chemokine-induced B-CLL cell survival. Overall, our data support the notion that homeostatic chemokines contribute to B-CLL resistance to cell death through inactivation of the transcription factor FOXO3a, which may represent a novel therapeutic target in this hematopoietic malignancy.
B 细胞慢性淋巴细胞白血病（B-CLL）细胞的特征是长寿的 CD5+ B 淋巴细胞积聚，其在体内的存活部分依赖于细胞因子和/或细胞外基质蛋白等外源性因素。稳态趋化因子是淋巴细胞迁移的关键介质。然而，它们在细胞信号传导和存活中的作用仍不清楚。在本研究中，我们研究了稳态趋化因子 CXCL12、CCL21、CCL19 和 CXCL13 在 B-CLL 细胞存活中的作用。使用从 26 名患者中分离的原发性白血病细胞，我们观察到每种趋化因子都能提高细胞存活率。趋化因子诱导 ERK1/2 和 p90RSK 以及 Akt 及其效应物 GSK3 和 FOXO3a 的磷酸化。一致地，针对丝裂原活化蛋白激酶/细胞外信号调节激酶和磷脂酰肌醇 3-激酶的抑制剂抑制趋化因子诱导的存活。此外，在原发性 B-CLL 细胞中进行的转染实验中，使用组成型活性突变形式的 FOXO3a 或针对 FOXO3a 的 siRNA，我们直接证明了 FOXO3a 在自发和趋化因子诱导的 B-CLL 细胞存活中的关键作用。总体而言，我们的数据支持这样的观点，即稳态趋化因子通过转录因子 FOXO3a 的失活促进 B-CLL 对细胞死亡的抗性，这可能代表这种造血恶性肿瘤的一个新的治疗靶点。
