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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. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-09-047043v1 109/8/3462    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Román-Gómez, J. Articles by Prosper, F. Search for Related Content PubMed PubMed Citation Articles by Román-Gómez, J. Articles by Prosper, F. Related Collections Oncogenes and Tumor Suppressors Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  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). CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Win-WNT pathway in ALL Gertjan J. L. Kaspers Blood 2007 109: 3135-3136. [Full Text] [PDF] This article has been cited by other articles: R. G. James, T. L. Biechele, W. H. Conrad, N. D. Camp, D. M. Fass, M. B. Major, K. Sommer, X. Yi, B. S. Roberts, M. A. Cleary, et al. Bruton's Tyrosine Kinase Revealed as a Negative Regulator of Wnt-{beta}-Catenin Signaling Sci. Signal., May 26, 2009; 2(72): ra25 - ra25. [Abstract] [Full Text] [PDF] X. Agirre, A. Vilas-Zornoza, A. Jimenez-Velasco, J. I. Martin-Subero, L. Cordeu, L. Garate, E. San Jose-Eneriz, G. Abizanda, P. Rodriguez-Otero, P. Fortes, et al. Epigenetic Silencing of the Tumor Suppressor MicroRNA Hsa-miR-124a Regulates CDK6 Expression and Confers a Poor Prognosis in Acute Lymphoblastic Leukemia Cancer Res., May 15, 2009; 69(10): 4443 - 4453. [Abstract] [Full Text] [PDF] M. E. Figueroa, B. J. Wouters, L. Skrabanek, J. Glass, Y. Li, C. A. J. Erpelinck-Verschueren, A. W. Langerak, B. Lowenberg, M. Fazzari, J. M. Greally, et al. Genome-wide epigenetic analysis delineates a biologically distinct immature acute leukemia with myeloid/T-lymphoid features Blood, March 19, 2009; 113(12): 2795 - 2804. [Abstract] [Full Text] [PDF] J. Roman-Gomez, X. Agirre, A. Jimenez-Velasco, V. Arqueros, A. Vilas-Zornoza, P. Rodriguez-Otero, I. Martin-Subero, L. Garate, L. Cordeu, E. San Jose-Eneriz, et al. Epigenetic Regulation of MicroRNAs in Acute Lymphoblastic Leukemia J. Clin. Oncol., March 10, 2009; 27(8): 1316 - 1322. [Abstract] [Full Text] [PDF] E. Marston, V. Weston, J. Jesson, E. Maina, C. McConville, A. Agathanggelou, A. Skowronska, K. Mapp, K. Sameith, J. E. Powell, et al. Stratification of pediatric ALL by in vitro cellular responses to DNA double-strand breaks provides insight into the molecular mechanisms underlying clinical response Blood, January 1, 2009; 113(1): 117 - 126. [Abstract] [Full Text] [PDF] P. Gelebart, M. Anand, H. Armanious, A. C. Peters, J. Dien Bard, H. M. Amin, and R. Lai Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma Blood, December 15, 2008; 112(13): 5171 - 5179. [Abstract] [Full Text] [PDF] X. Agirre, A. Jimenez-Velasco, E. San Jose-Eneriz, L. Garate, E. Bandres, L. Cordeu, O. Aparicio, B. Saez, G. Navarro, A. Vilas-Zornoza, et al. Down-Regulation of hsa-miR-10a in Chronic Myeloid Leukemia CD34+ Cells Increases USF2-Mediated Cell Growth Mol. Cancer Res., December 1, 2008; 6(12): 1830 - 1840. [Abstract] [Full Text] [PDF] R. W.J. Groen, M. E.C.M. Oud, E. J.M. Schilder-Tol, M. B. Overdijk, D. ten Berge, R. Nusse, M. Spaargaren, and S. T. Pals Illegitimate WNT Pathway Activation by {beta}-Catenin Mutation or Autocrine Stimulation in T-Cell Malignancies Cancer Res., September 1, 2008; 68(17): 6969 - 6977. [Abstract] [Full Text] [PDF] B. Novakovic, V. Rakyan, H.K. Ng, U. Manuelpillai, C. Dewi, N.C. Wong, R. Morley, T. Down, S. Beck, J.M. Craig, et al. Specific tumour-associated methylation in normal human term placenta and first-trimester cytotrophoblasts Mol. Hum. Reprod., September 1, 2008; 14(9): 547 - 554. [Abstract] [Full Text] [PDF] V. Jovanovic, A.-S. Dugast, J.-M. Heslan, J. Ashton-Chess, M. Giral, N. Degauque, A. Moreau, A. Pallier, E. Chiffoleau, D. Lair, et al. Implication of Matrix Metalloproteinase 7 and the Noncanonical Wingless-Type Signaling Pathway in a Model of Kidney Allograft Tolerance Induced by the Administration of Anti-Donor Class II Antibodies J. Immunol., February 1, 2008; 180(3): 1317 - 1325. [Abstract] [Full Text] [PDF] J. Ying, H. Li, Y.-W. Chen, G. Srivastava, Z. Gao, and Q. Tao WNT5A is epigenetically silenced in hematologic malignancies and inhibits leukemia cell growth as a tumor suppressor Blood, December 1, 2007; 110(12): 4130 - 4131. [Full Text] [PDF] M. van Noort, F. Weerkamp, H. C. Clevers, and F. J. T. Staal Wnt signaling and phosphorylation status of {beta}-catenin: importance of the correct antibody tools Blood, October 1, 2007; 110(7): 2778 - 2779. [Full Text] [PDF]

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