title: Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia.
abstract: Activation of the Wnt/beta-catenin signaling pathway is a hallmark of a number of solid tumors. We analyzed the regulation of the Wnt/beta-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 beta-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).
authors.affiliation: Department of Hematology, Hospital Reina Sofia, Cordoba, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Román-Gómez
authors.forename: Lucia
authors.initials: L
authors.lastname: Cordeu
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.forename: Antonio
authors.initials: A
authors.lastname: Jiménez-Velasco
authors.forename: Edurne
authors.initials: E
authors.lastname: San José-Eneriz
authors.forename: Leire
authors.initials: L
authors.lastname: Garate
authors.forename: María José
authors.initials: MJ
authors.lastname: Calasanz
authors.forename: Anabel
authors.initials: A
authors.lastname: Heiniger
authors.forename: Antonio
authors.initials: A
authors.lastname: Torres
authors.forename: Felipe
authors.initials: F
authors.lastname: Prosper
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D011794:Quercetin / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D000077209:Decitabine; D011794:Quercetin; D001374:Azacitidine