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

Oncogene volume 26, pages 7081–7091 (2007)Cite this article

Abstract

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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Acknowledgements

We thank Frederic Brau for its help on confocal microscopy, Eric W-F Lam and Anne Brunet for Bim promoter and FRE luciferase reporter constructs, respectively, and Sophie Raynaud for helpful discussions. This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Fondation pour la Recherche Médicale, the Association pour la Recherche sur le Cancer and the Groupe d'Etudes et de Recherche Clinique, Biologique et Thérapeutique. ME is a recipient of a research fellowship from the Association pour la Recherche sur le Cancer (ML/MLD/CM-A03.04) and PYJ is a recipient of a research fellowship from the Fondation pour la Recherche Médicale.

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Author notes

  1. M Ticchioni, M Essafi, M Deckert and A Bernard: These authors contributed equally to this work.

Authors and Affiliations

  1. Département d'Immunologie, Hôpital de l'Archet, Université de Nice-Sophia Antipolis, Nice, France

    M Ticchioni & A Bernard

  2. Inserm, UMR576, Hôpital de l'Archet, Nice, France

    M Ticchioni, M Essafi, M Deckert & A Bernard

  3. Département de Médecine Interne, Hôpital de l'Archet, Université de Nice-Sophia Antipolis, Nice, France

    P Y Jeandel

  4. Département d'Hématologie, Groupe Hospitalier de la Pitié-Salpétrière, Université Pierre et Marie Curie, Paris, France

    F Davi

  5. Département d'Hématologie, Hôpital de l'Archet, Université de Nice-Sophia Antipolis, Nice, France

    J P Cassuto

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  1. M Ticchioni
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Correspondence to M Ticchioni.

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Ticchioni, M., Essafi, M., Jeandel, P. et al. Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a. Oncogene 26, 7081–7091 (2007). https://doi.org/10.1038/sj.onc.1210519

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