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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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Submitted September 12, 2006
Accepted November 27, 2006
Epigenetic regulation of WNT signaling pathway in acute lymphoblastic leukemia
Jose Roman-Gomez, Lucia Cordeu, Xabier Agirre, Antonio Jimenez-Velasco, Edurne San Jose-Eneriz, Leire Garate, Maria Jose Calasanz, Anabel Heiniger, Antonio Torres, and Felipe Prosper*
Department of Hematology, Hospital Reina Sofia, Cordoba, Spain
Foundation for Applied Medical Research, Clinica Universitaria, Universidad de Navarra, Pamplona, Spain
Department of Hematology, Hospital Carlos Haya, Malaga, Spain
Department of Genetics, School of Sciences, University of Navarra, Pamplona, Spain
* Corresponding author; email: fprosper{at}unav.es.
Activation of the Wnt/ -catenin signaling pathway is a hallmark of a number of solid tumors. We analyzed the regulation of the Wnt/-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, Wif-1, Dkk-3 and Hdpr-1 was downregulated 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 upregulation of the Wnt target genes Wnt-16, Fz-3, Tcf-1, Lef-1 and cyclin D1 in cell lines and samples and the nuclear localization of -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 newly diagnosed ALL patients, abnormal methylation of Wnt inhibitors was associated with decreased 10 year DFS (25% versus 66% respectively, P < 0.0001) and OS (28% versus 61% respectively, P = 0.0003). 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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