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dc.contributor.authorLugthart, S*
dc.contributor.authorFigueroa, M*
dc.contributor.authorBindels, E*
dc.contributor.authorSkrabanek, L*
dc.contributor.authorValk, P J M*
dc.contributor.authorLi, Y*
dc.contributor.authorMeyer, Stefan*
dc.contributor.authorErpelinck-Verschueren, C*
dc.contributor.authorGreally, J*
dc.contributor.authorLöwenberg, B*
dc.contributor.authorMelnick, A*
dc.contributor.authorDelwel, R*
dc.date.accessioned2012-01-09T22:38:32Z
dc.date.available2012-01-09T22:38:32Z
dc.date.issued2011-01-06
dc.identifier.citationAberrant DNA hypermethylation signature in acute myeloid leukemia directed by EVI1. 2011, 117 (1):234-41 Blooden
dc.identifier.issn1528-0020
dc.identifier.pmid20855866
dc.identifier.doi10.1182/blood-2010-04-281337
dc.identifier.urihttp://hdl.handle.net/10541/201086
dc.description.abstractDNA 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.
dc.language.isoenen
dc.subject.meshAdolescent
dc.subject.meshAdult
dc.subject.meshAged
dc.subject.meshBlotting, Western
dc.subject.meshChromatin Immunoprecipitation
dc.subject.meshDNA (Cytosine-5-)-Methyltransferase
dc.subject.meshDNA Methylation
dc.subject.meshDNA, Neoplasm
dc.subject.meshDNA-Binding Proteins
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshLeukemia, Myeloid, Acute
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshPolymerase Chain Reaction
dc.subject.meshPromoter Regions, Genetic
dc.subject.meshProto-Oncogenes
dc.subject.meshTranscription Factors
dc.subject.meshYoung Adult
dc.titleAberrant DNA hypermethylation signature in acute myeloid leukemia directed by EVI1.en
dc.typeArticleen
dc.contributor.departmentDepartment of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.en
dc.identifier.journalBlooden
html.description.abstractDNA 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.


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