title: Hypermethylation of CpG sites at the promoter region is associated with deregulation of mitochondrial ATPsyn-β and chemoresistance in acute myeloid leukemia.
abstract: BACKGROUND
  Aberrant DNA methylation status of some genes has been shown to be involved in chemoresistance of acute myeloid leukemia (AML). We have recently found that down-regulation of the β subunit of mitochondrial ATP synthase (ATPsyn-β) leads to adriamycin resistance in acute and chronic myeloid leukemia cells, and hypermethylation of the ATPsyn-β gene promoter is associated with chemoresistance in chronic myeloid leukemia.
  
  
  OBJECTIVE
  To further investigate the relationship between methylation of ATPsyn-β gene, mRNA expression as well as chemoresistance in AML.
  
  
  METHODS
  Quantitative RT-PCR and methylation specific PCR were performed to assess mRNA expression and methylation status of ATPsyn-β gene on primary bone marrow nuclear cells (BMMCs), and cell proliferation assay was used to determine the sensitivity of BMMCs to adriamycin.
  
  
  RESULTS
  Hypermethylation status of ATPsyn-β gene promoter existed in those relapsed/refractory AML patients, and this hypermethylation of the gene was associated with a suppressed mRNA expression levels. Four patients at diagnosis and relapse underwent gene methylation status shift from hypermethylation to hypomethylation, which was accompanied by reduced mRNA expression of the gene. 5-azacitidine(5-Aza)- a demethylating agent, could restore ATPsyn-β mRNA expression and increase the adriamycin sensitivity of primary leukemic cells from seven relapsed/ refractory AML patients.
  
  
  CONCLUSIONS
  Hypermethylation of ATPsyn-β gene promoter is associated with a down-regulated mRNA expression and chemoresistance in AML patients.
authors.affiliation: Division of Hematology, Institution of Molecular Hematology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, China.|Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Jingke
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Hematology, Institution of Molecular Hematology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Division of Hematology, Institution of Molecular Hematology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Li
authors.affiliation: Division of Hematology, Institution of Molecular Hematology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Zijian
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Hematology, Institution of Molecular Hematology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Deng
authors.affiliation: Division of Hematology, Institution of Molecular Hematology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Guangsen
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000494:pharmacology; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012008:Recurrence; D012074:Remission Induction; D055815:Young Adult
chemical_list: D025261:Mitochondrial Proton-Translocating ATPases; D001374:Azacitidine
keywords: Methylation; acute myeloid leukemia; chemoresistance; mitochondrial ATP synthase