Abstract
The Wnt family of secreted glycoproteins is widely involved in cell proliferation, differentiation and oncogenesis. Many Wnt signaling genes are upregulated and activated in chronic lymphocytic leukemia. Less is known concerning acute leukemia. One subtype of acute lymphoblastoid leukemia (ALL) is characterized by a t(1;19) chromosomal translocation resulting in a fusion protein E2A–Pbx1 that promotes transformation and leukemogenesis. Wnt16 has been shown to be targeted by E2A–Pbx1. We performed a differential gene expression array in acute leukemia cell lines displaying or not displaying the t(1;19) translocation. We found that Wnt16 and many Wnt signaling-related genes were upregulated in the translocation-containing cells. As two isoforms of Wnt16, Wnt16a and Wnt16b, have been recently identified, we demonstrated by using RT–PCR and Western blot that Wnt16b (and not Wnt16a) is overexpressed in t(1;19)-containing cell lines. We then directly addressed the role played by both isoforms in this type of leukemia. Using specific short interfering RNA (siRNA) and an anti-Wnt16 antibody, we showed that targeted-Wnt16b inhibition leads to apoptotic cell death. We also demonstrated that Wnt16b mediates its effect through the canonical Wnt pathway involving dishevelled-2, β-catenin and survivin. We thus propose that Wnt16 plays an important role in leukemogenesis, raising its therapeutic interest.
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Acknowledgements
We thank Drs Mignon Loh and Kevin Shannon for providing us RCH-ACV cell lines, Sarah Meles and the flow cytometry laboratory at UCSF Cancer Center for flow cytometry analysis and the genome core analysis laboratory at UCSF Cancer Center for sequence analysis. Wnt16 cDNA plasmid was kindly provided by Dr Yingzi Yang at the NHGRI/NIH. This work was supported by the Larry Hall memorial trust, the Kazan, McClain, Edises, Abrams, Fernandez, Lyons & Farrise Foundation and the Fondation pour la Recherche Medicale (JM) and Association Nationale pour le Traitement A Domicile des Insuffisants Respiratoires (JM).
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Mazieres, J., You, L., He, B. et al. Inhibition of Wnt16 in human acute lymphoblastoid leukemia cells containing the t(1;19) translocation induces apoptosis. Oncogene 24, 5396–5400 (2005). https://doi.org/10.1038/sj.onc.1208568
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DOI: https://doi.org/10.1038/sj.onc.1208568
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