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 Blood, 15 April 2007, Vol. 109, No. 8, pp. 3462-3469.
Prepublished online as a Blood First Edition Paper on December 5, 2006; DOI 10.1182/blood-2006-09-047043.

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NEOPLASIA

Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia

José Román-Gómez1, Lucia Cordeu2, Xabier Agirre2, Antonio Jiménez-Velasco3, Edurne San José-Eneriz2, Leire Garate2, María José Calasanz4, Anabel Heiniger3, Antonio Torres1, and Felipe Prosper2

1 Department of Hematology, Hospital Reina Sofia, Cordoba, Spain; 2 Foundation for Applied Medical Research, Division of Cancer and Area of Cell Therapy and Hematology Service, Clínica Universitaria, Universidad de Navarra, Spain; 3 Department of Hematology, Hospital Carlos Haya, Malaga, Spain; 4 Department of Genetics, School of Sciences, University of Navarra, Pamplona, Spain

Activation of the Wnt/ß-catenin signaling pathway is a hallmark of a number of solid tumors. We analyzed the regulation of the Wnt/ß-catenin pathway in acute lymphoblastic leukemia (ALL) and its role in the pathogenesis of the disease. We found that expression of the Wnt inhibitors sFRP1, sFRP2, sFRP4, sFRP5, WIF1, Dkk3, and Hdpr1 was down-regulated due to abnormal promoter methylation in ALL cell lines and samples from patients with ALL. Methylation of Wnt inhibitors was associated with activation of the Wnt-signaling pathway as demonstrated by the up-regulation of the Wnt target genes WNT16, FZ3, TCF1, LEF1, and cyclin D1 in cell lines and samples and the nuclear localization of ß-catenin in cell lines. Treatment of ALL cells with the Wnt inhibitor quercetin or with the demethylating agent 5-aza-2'-deoxycytidine induced an inactivation of the Wnt pathway and induced apoptosis of ALL cells. Finally, in a group of 261 patients with newly diagnosed ALL, abnormal methylation of Wnt inhibitors was associated with decreased 10-year disease-free survival (25% versus 66% respectively, P < .001) and overall survival (28% versus 61% respectively, P = .001). Our results indicate a role of abnormal Wnt signaling in ALL and establish a group of patients with a significantly worse prognosis (methylated group).


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