title: DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML.
abstract: BACKGROUND
  Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are neoplastic disorders of hematopoietic stem cells. DNA methyltransferase inhibitors, 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine), benefit some MDS/AML patients. However, the role of DNA methyltransferase inhibitor-induced DNA hypomethylation in regulation of gene expression in AML is unclear.
  
  
  RESULTS
  We compared the effects of 5-azacytidine on DNA methylation and gene expression using whole-genome single-nucleotide bisulfite-sequencing and RNA-sequencing in OCI-AML3 cells. For data analysis, we used an approach recently developed for discovery of differential patterns of DNA methylation associated with changes in gene expression, that is tailored to single-nucleotide bisulfite-sequencing data (Washington University Interpolated Methylation Signatures). Using this approach, we find that a subset of genes upregulated by 5-azacytidine are characterized by 5-azacytidine-induced signature methylation loss flanking the transcription start site. Many of these genes show increased methylation and decreased expression in OCI-AML3 cells compared to normal hematopoietic stem and progenitor cells. Moreover, these genes are preferentially upregulated by decitabine in human primary AML blasts, and control cell proliferation, death, and development.
  
  
  CONCLUSIONS
  Our approach identifies a set of genes whose methylation and silencing in AML is reversed by DNA methyltransferase inhibitors. These genes are good candidates for direct regulation by DNA methyltransferase inhibitors, and their reactivation by DNA methyltransferase inhibitors may contribute to therapeutic activity.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Lund
authors.forename: John J
authors.initials: JJ
authors.lastname: Cole
authors.forename: Nathan D
authors.initials: ND
authors.lastname: VanderKraats
authors.forename: Tony
authors.initials: T
authors.lastname: McBryan
authors.forename: Nikolay A
authors.initials: NA
authors.lastname: Pchelintsev
authors.forename: William
authors.initials: W
authors.lastname: Clark
authors.forename: Mhairi
authors.initials: M
authors.lastname: Copland
authors.forename: John R
authors.initials: JR
authors.lastname: Edwards
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017423:Sequence Analysis, RNA
chemical_list: D004791:Enzyme Inhibitors; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine