title: Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation.
abstract: Nuclear localization of non-phosphorylated, active beta-catenin is a measure of Wnt pathway activation and is associated with adverse outcome in patients with acute myeloid leukemia (AML). While genetic alterations of the Wnt pathway are infrequent in AML, inhibitors of this pathway are silenced by promoter methylation in other malignanices. Leukemia cell lines were examined for Wnt pathway inhibitor methylation and total beta-catenin levels, and had frequent methylation of Wnt inhibitors and upregulated beta-catenin by Western blot and immunofluorescence. One hundred sixty-nine AML samples were examined for methylation of Wnt inhibitor genes. Diagnostic samples from 72 patients with normal cytogenetics who received standard high-dose induction chemotherapy were evaluated for associations between methylation and event-free or overall survival. Extensive methylation of Wnt pathway inhibitor genes was observed in cell lines, and 89% of primary AML samples had at least one methylated gene: DKK1 (16%), DKK3 (8%), RUNX3 (27%), sFRP1 (34%), sFRP2 (66%), sFRP4 (9%), sFRP5 (54%), SOX17 (29%), and WIF1 (32%). In contrast to epithelial tumors, methylation of APC (2%) and RASSF1A (0%) was rare. In patients with AML with normal cytogenetics, sFRP2 and sFRP5 methylation at the time of diagnosis was associated with an increased risk of relapse, and sFRP2 methylation was associated with an increased risk for death. In patients with AML: (a) there is a high frequency of Wnt pathway inhibitor methylation; (b) Wnt pathway inhibitor methylation is distinct from that observed in epithelial malignancies; and (c) methylation of sFRP2 and sFRP5 may predict adverse clinical outcome in patients with normal karyotype AML.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Griffiths
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Craig
authors.initials: C
authors.lastname: Hooker
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Helai P
authors.initials: HP
authors.lastname: Mohammad
authors.forename: Ying
authors.initials: Y
authors.lastname: Ye
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Hetty E
authors.initials: HE
authors.lastname: Carraway
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019175:DNA Methylation; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015398:Signal Transduction; D015996:Survival Rate; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005136:Eye Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D051153:Wnt Proteins; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C118511:SFRP5 protein, human
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