Aberrant DNA hypermethylation signature in acute myeloid leukemia directed by EVI1

Sanne Lugthart, Maria E. Figueroa, Eric Bindels, Lucy Skrabanek, Peter J M Valk, Yushan Li, Stefan Meyer, Claudia Erpelinck-Verschueren, John Greally, Bob Löwenberg, Ari Melnick, Ruud Delwel

    Research output: Contribution to journalArticlepeer-review

    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. © 2011 by The American Society of Hematology.
    Original languageEnglish
    Pages (from-to)234-241
    Number of pages7
    JournalBlood
    Volume117
    Issue number1
    DOIs
    Publication statusPublished - 6 Jan 2011

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