title: Distinct association between aberrant methylation of Wnt inhibitors and genetic alterations in acute myeloid leukaemia.
abstract: BACKGROUND
  Aberrant activation of Wnt signalling through hypermethylation of Wnt inhibitor genes is involved in several human malignancies, including acute myeloid leukaemia (AML). It remains unclear whether hypermethylation of Wnt inhibitors is associated with molecular gene mutations in the development of AML.
  
  
  METHODS
  We investigated the association of the promoter hypermethylation of six Wnt inhibitors (Wif-1, SFRP1, SFRR2, SFRP4, SFRP5, and DKK1) with gene aberrations in the leukaemogenesis of 269 AML patients.
  
  
  RESULTS
  In total, 166 patients (61.7%) had hypermethylation of at least one Wnt inhibitor. The majority (68.5%) of patients with Wnt inhibitor hypermethylation had concurrent Class II gene mutations that affect transcription factors or cofactors. There was a close association of Wif-1 hypermethylation with t(15;17) (P=0.0005) and CEBPA mutation (P<0.0001), DKK1 hypermethylation with t(8;21) (P<0.0001) and ASXL1 mutation (P=0.0078), SFRP-1 hypermethylation with t(8;21) (P<0.0001), SFRP-2 hypermethylation with AML1/RUNX1 mutation (P=0.0012), and SFRP-5 hypermethylation with MLL/PTD (P=0.0505). On the other side, hypermethylation of Wnt inhibitors was always negatively associated with NPM1 mutation and FLT3/ITD.
  
  
  CONCLUSIONS
  There was distinct association between hypermethylation of individual Wnt inhibitors and specific gene aberrations, especially Class II mutations. The Wnt inhibitor hypermethylation might interact with genetic alterations in the leukaemogenesis.
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: H-A
authors.initials: HA
authors.lastname: Hou
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Kuo
authors.forename: C-Y
authors.initials: CY
authors.lastname: Liu
authors.forename: M C
authors.initials: MC
authors.lastname: Lee
authors.forename: J-L
authors.initials: JL
authors.lastname: Tang
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chen
authors.forename: W-C
authors.initials: WC
authors.lastname: Chou
authors.forename: C-F
authors.initials: CF
authors.lastname: Huang
authors.forename: F-Y
authors.initials: FY
authors.lastname: Lee
authors.forename: M-C
authors.initials: MC
authors.lastname: Liu
authors.forename: M
authors.initials: M
authors.lastname: Yao
authors.forename: H-F
authors.initials: HF
authors.lastname: Tien
mesh_terms: D000328:Adult; D019175:DNA Methylation; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009154:Mutation; D000090243:Nucleophosmin; D016133:Polymerase Chain Reaction; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C000716967:NPM1 protein, human; D051153:Wnt Proteins; D000090243:Nucleophosmin
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