Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a.
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.
Ticchioni
M
M
Département d'Immunologie, Hôpital de l'Archet, Université de Nice-Sophia Antipolis, Nice, France. michel.ticchioni@unice.fr
Essafi
M
M
Jeandel
P Y
PY
Davi
F
F
Cassuto
J P
JP
Deckert
M
M
Bernard
A
A
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D018925:Chemokines / Q000502:physiology*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology
D018925:Chemokines; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors