title: Aberrant promoter methylation of Dab2 gene in myelodysplastic syndrome.
abstract: OBJECTIVE
  Human Disabled-2 (Dab2), a putative tumor suppressor gene, is frequently down-regulated in human tumors. This study aims to explore the association between Dab2 methylation status and expression in newly diagnosed myelodysplastic syndrome (MDS) patients and patients who received 5-aza-2'-deoxycytidine (decitabine) treatment, so as to determine the effect of Dab2 in the pathogenesis of MDS.
  
  
  METHODS
  Methylation-specific polymerase chain reaction and bisulfite sequencing were used to detect the methylation status of Dab2 gene. Dab2 expression was investigated by using fluorescence quantitation RT-PCR (FQRT-PCR) and western blot analysis.
  
  
  RESULTS
  Hypermethylation of Dab2 gene was present in 50.6% of patients with MDS and was significantly correlated with the down-regulation of Dab2 mRNA and protein expression. There was a significant difference in methylation frequency between refractory anemia/refractory anemia with ringed sideroblasts/MDS associated with isolated del (5q) (RA/RARS/5q-) group (33.3%) and refractory anemia with excess blasts-1/-2 (RAEB-1/RAEB-2) group (73.3%). Significant difference was also observed between refractory cytopenia with multiline dysplasia group (37.8%) and RAEB-1/RAEB-2 group. In addition, higher frequency of hypermethylation was observed in intermediate-2-/high-risk group, compared to low-risk/intermediate-1-risk group (75.0% vs. 40.0%). Demethylating agent 5-aza-2'-deoxycytidine treatment could partly reverse hypermethylation and, hence, restore the expression of Dab2 gene.
  
  
  CONCLUSIONS
  The Dab2 gene is inactivated in MDS in part by DNA methylation, and the suppression of Dab2 expression by DNA methylation may play a role in the development of MDS.
authors.affiliation: Department of Hematology, The Sixth Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Yang
authors.forename: Qingxia
authors.initials: Q
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Chunkang
authors.initials: C
authors.lastname: Chang
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002460:Cell Line; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007621:Karyotyping; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D001374:Azacitidine