title: Aberrant DNA hypermethylation signature in acute myeloid leukemia directed by EVI1.
abstract: DNA methylation patterns are frequently dysregulated in cancer, although little is known of the mechanisms through which specific gene sets become aberrantly methylated. The ecotropic viral integration site 1 (EVI1) locus encodes a DNA binding zinc-finger transcription factor that is aberrantly expressed in a subset of acute myeloid leukemia (AML) patients with poor outcome. We find that the promoter DNA methylation signature of EVI1 AML blast cells differs from those of normal CD34(+) bone marrow cells and other AMLs. This signature contained 294 differentially methylated genes, of which 238 (81%) were coordinately hypermethylated. An unbiased motif analysis revealed an overrepresentation of EVI1 binding sites among these aberrantly hypermethylated loci. EVI1 was capable of binding to these promoters in 2 different EVI1-expressing cell lines, whereas no binding was observed in an EVI1-negative cell line. Furthermore, EVI1 was observed to interact with DNA methyl transferases 3A and 3B. Among the EVI1 AML cases, 2 subgroups were recognized, of which 1 contained AMLs with many more methylated genes, which was associated with significantly higher levels of EVI1 than in the cases of the other subgroup. Our data point to a role for EVI1 in directing aberrant promoter DNA methylation patterning in EVI1 AMLs.
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Lugthart
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.forename: Eric
authors.initials: E
authors.lastname: Bindels
authors.forename: Lucy
authors.initials: L
authors.lastname: Skrabanek
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Yushan
authors.initials: Y
authors.lastname: Li
authors.forename: Stefan
authors.initials: S
authors.lastname: Meyer
authors.forename: Claudia
authors.initials: C
authors.lastname: Erpelinck-Verschueren
authors.forename: John
authors.initials: J
authors.lastname: Greally
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011519:Proto-Oncogenes / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; D014157:Transcription Factors; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C063575:MECOM protein, human