title: Methylation of Wnt antagonist genes: a useful prognostic marker for myelodysplastic syndrome.
abstract: Activation of the Wnt signaling pathway has been implicated in the pathogenesis of many tumors as well as in leukemia. However, its role in myelodysplastic syndrome (MDS) is unknown. In this study, we employed methylation-specific PCR to examine the methylation status of six Wnt antagonist genes in 144 MDS patients and in the MDS cell line SKM-1. We also used real-time PCR to examine the expression of Wnt antagonist genes and Wnt pathway genes in the SKM-1 cell line after treatment with 5-aza-2'-deoxycytidine. We found that methylation of the gene promoters of each of the six genes were observed in MDS patients at the following methylation frequencies: 41 % for sFRP1, 89.6 % for sFRP2, 43.1 % for sFRP4, 50.7 % for sFRP5, 44.4 % for DKK-1, and 69.4 % for DKK-3. In the SKM-1 cell line, the gene promoters sFRP1, sFRP2, sFRP5, DKK-1, and DKK-3 were methylated, while sFRP4 was not methylated. Treatment of the SKM-1 cell line with 5-aza-2'-deoxycytidine induced re-expression of methylated Wnt antagonists and inactivation of the Wnt pathway. Survival analysis showed that methylation status of sFRP1, sFRP4, and sFRP5 was associated with worse survival in MDS and sFRP5 methylation also predicted a high risk of leukemia evolution (P = 0.018). Our results indicate that epigenetic regulation of the Wnt pathway in MDS cell line, and the methylation status of Wnt antagonists predicts prognoses of MDS patients.
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, No.188 Shi Zi Street, Suzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Wang
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Wu
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: Lin
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000737:chemistry / Q000648:ultrastructure; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002467:Cell Nucleus / Q000737:chemistry; D018925:Chemokines; D003593:Cytoplasm / Q000737:chemistry; D019175:DNA Methylation; D000077209:Decitabine; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012720:Severity of Illness Index; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D060449:Wnt Signaling Pathway / Q000235:genetics*; D055815:Young Adult; D051176:beta Catenin / Q000032:analysis; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001374:Azacitidine; D018925:Chemokines; D000077209:Decitabine; D005136:Eye Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human; C501126:DKK1 protein, human; C498624:DKK3 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109618:SFRP2 protein, human; C118723:SFRP4 protein, human; C118511:SFRP5 protein, human