Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia.
Activation of the Wnt signaling pathway has been implicated recently in the pathogenesis of leukemia. We studied the function of epigenetic regulation of the Wnt pathway and its prognostic relevance in acute myelogenous leukemia (AML). We used a methylation-specific polymerase chain reaction approach to analyze the promoter methylation status of a panel of Wnt antagonists including sFRP1, sFRP2, sFRP4, sFRP5, DKK1 and DKK3. Aberrant methylation of Wnt antagonists was detected in four AML cell lines and in up to 64% of AML marrow samples. Treatment of the cell lines with 5-aza-2'-deoxycytidine induced reexpression of methylated Wnt antagonists and inactivation of the Wnt pathway by downregulating the Wnt pathway genes cyclin D1, TCF1 and LEF1 and reducing nuclear localization of beta-catenin. In a subgroup of patients 60 years and younger with newly diagnosed AML and intermediate-risk cytogenetics, abnormal methylation of Wnt antagonists was associated with decreased 4-year relapse-free survival (28 vs 61%, respectively, P=0.03). Our results indicate a function of the epigenetic regulation of the Wnt pathway in predicting relapse in a subgroup of AML patients.
Valencia
A
A
Department of Hematology, Hospital Universitario La Fe, Valencia, Spain.
Román-Gómez
J
J
Cervera
J
J
Such
E
E
Barragán
E
E
Bolufer
P
P
Moscardó
F
F
Sanz
G F
GF
Sanz
M A
MA
D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D005260:Female; D019940:Genes, bcl-1; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015398:Signal Transduction; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
D064007:Ataxia Telangiectasia Mutated Proteins; D001374:Azacitidine; D018797:Cell Cycle Proteins; D000077209:Decitabine; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D051153:Wnt Proteins; C501126:DKK1 protein, human; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C576597:ATR protein, human