Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a

被引：0
作者：
M Ticchioni
M Essafi
P Y Jeandel
F Davi
J P Cassuto
M Deckert
A Bernard
机构：
[1] Hôpital de l'Archet,Département d'Immunologie
[2] Université de Nice-Sophia Antipolis,Département de Médecine Interne
[3] Inserm,Département d'Hématologie
[4] UMR576,Département d'Hématologie
[5] Hôpital de l'Archet,undefined
[6] Hôpital de l'Archet,undefined
[7] Université de Nice-Sophia Antipolis,undefined
[8] Groupe Hospitalier de la Pitié-Salpétrière,undefined
[9] Université Pierre et Marie Curie,undefined
[10] Hôpital de l'Archet,undefined
[11] Université de Nice-Sophia Antipolis,undefined
来源：
Oncogene | 2007年 / 26卷
关键词：
B-CLL; chemokines; survival; Akt; FOXO3a;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
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.
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页码：7081 / 7091
页数：10
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