期刊
BLOOD
卷 117, 期 1, 页码 234-241出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-04-281337
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资金
- National Institutes of Health [R8301-HD044078, GM007288]
- Dutch Cancer Society [EMCR 2006-522]
- European Hematology Association
- Koningin Wilhelmina Fonds
- American Society of Hematology
- American Institute for Cancer Research [8305-8297]
- Leukemia & Lymphoma Society [6196-09, 6196-8309]
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. (Blood. 2011;117(1):234-241)
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