title: Infrequent hypermethylation of WIF-1 promoter in BCR/ABL-negative myeloproliferative disorders.
abstract: OBJECTIVE
  The Wnt/β;-catenin signaling pathway is important in the pathogenesis of hematological malignancies. Wnt inhibitory factor-1 (WIF-1) is a negative regulator of Wnt signaling that is frequently downregulated by hypermethylation of the WIF-1 promoter in acute promyelocytic leukemia (APL) and other malignancies. On the other hand, an acquired mutation in JAK2 tyrosine kinase involving a V617F amino-acid substitution shows a strong association with the pathogenesis of BCR/ABL-negative MPD. This is the first study to examine the relationship between WIF-1 methylation and the existence of JAK2V617F mutation in the pathogenesis of BCR/ABL-negative myeloproliferative disorders (MPD) including polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis, and chronic myeloproliferative disease, unclassifiable.
  
  
  METHODS
  We evaluated 49 newly diagnosed and previously treated patients with MPD in chronic phase. Bone marrow (BM) mononuclear cells, when available, or PB mononuclear cells of patients were used for the analysis. The mutation status of JAK2 was analyzed using sequencing analysis. The methylation status of the WIF-1 promoter was analyzed by methylation-specific polymerase chain reaction (MSP).
  
  
  RESULTS
  The JAK2V617F mutation was found in 23/49 patients (46.9%) with BCR/ABL-negative MPD, while WIF-1 methylation was detected in 1/49 patients (2.0%).
  
  
  CONCLUSIONS
  WIF-1 is infrequently methylated in BCR/ABL-negative MPD.
authors.affiliation: Department of Hematology/Oncology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Rikio
authors.initials: R
authors.lastname: Suzuki
authors.forename: Makoto
authors.initials: M
authors.lastname: Onizuka
authors.forename: Minoru
authors.initials: M
authors.lastname: Kojima
authors.forename: Masako
authors.initials: M
authors.lastname: Shimada
authors.forename: Kosuke
authors.initials: K
authors.lastname: Tsuboi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawada
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002908:Chronic Disease; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008745:Methylation; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D012097:Repressor Proteins; C485569:WIF1 protein, human; D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2