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A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemia

Oncogene volume 25, pages 3113–3122 (2006)Cite this article

Abstract

Relapses following chemotherapy are a major hindrance to patients’ survival in acute myeloid leukemia (AML). To investigate the role of the hematopoietic niche in the chemoresistance of leukemic cells, we examined two pathways: one mediated by adhesion molecules/integrins, and the other by soluble factors of the morphogen Wnt pathway. In our study, both the adhesion of leukemic blasts to fibronectin and the addition of Wnt antagonists induced, independently, resistance of AML cells to daunorubicin in a cell survival assay. Using pharmacological inhibitors and siRNA, we showed that both resistance pathways required the activity of the glycogen synthase kinase 3β (GSK3β). Moreover, the AML cell protection downstream of GSK3β was mediated by NF-κB. A link between the adhesion and the Wnt pathway was found, as adhesion of U937 on human osteoblasts, a component of the hematopoietic niche, triggered the secretion of the Wnt antagonist sFRP-1 and supported resistance to daunorubicin. The osteoblast-conditioned medium could also confer chemoresistance to U937 cells cultured in suspension, and this cell protective effect was abrogated after depletion of sFRP-1. In the context of this potential double in vivo resistance, modulators of the common signal GSK3β and of its target NF-κB could represent important novel therapeutic tools.

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Acknowledgements

We acknowledge Dr Jeff Rubin for sFRP-1 purchase and scientific advices, Pr Guy Laurent for supporting CAM-DR studies and Dr Fatima L’Faqihi for technical assistance in FACS experiments. This work was financially supported by Association pour la Recherche contre le Cancer (Grant No. 3638); Association Laurette Fugain, France.

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Authors and Affiliations

  1. Département d’Oncogenèse et Signalisation Cellulaire dans les Cellules Hématopoïétiques, Institut National de la Santé et de la Recherche Médicale Unité 563, Centre Hospitalier Universitaire Purpan, Toulouse, France

    F De Toni, C Racaud-Sultan, G Chicanne, V Mansat-De Mas, C Demur, M Allouche, B Payrastre, S Manenti & L Ysebaert

  2. Laboratoire d’Hématologie, Institut National de la Santé et de la Recherche Médicale Unité 563, Centre Hospitalier Universitaire Purpan, Toulouse, France

    V Mansat-De Mas & C Demur

  3. Département Lipoprotéines et Médiateurs lipidiques, Institut Fédératif de Recherche (IFR)30, Institut National de la Santé et de la Recherche Médicale Unité 563, Centre Hospitalier Universitaire Purpan, Toulouse, France

    C Cariven, F Mesange & J-P Salles

  4. Service d’Hématologie Clinique, Institut National de la Santé et de la Recherche Médicale Unité 563, Centre Hospitalier Universitaire Purpan, Toulouse, France

    L Ysebaert

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  1. F De Toni
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Correspondence to C Racaud-Sultan.

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De Toni, F., Racaud-Sultan, C., Chicanne, G. et al. A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemia. Oncogene 25, 3113–3122 (2006). https://doi.org/10.1038/sj.onc.1209346

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