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Epigenetic silencing of Bcl-2, CEBPA and p14(ARF) by the AML1-ETO oncoprotein contributing to growth arrest and differentiation block in the U937 cell line
- Source :
- Oncology reports. 30(1)
- Publication Year :
- 2013
-
Abstract
- The AML1-ETO fusion transcription factor generated by the t(8;21) translocation is considered to deregulate the expression of genes that are crucial for normal differentiation and proliferation of hematopoietic progenitors, resulting in acute myelogenous leukemia by recruiting co-repressor complexes to DNA. To investigate the role of AML1-ETO in leukemogenesis, we transfected the cloned AML1-ETO cDNA and expressed the AML1-ETO protein in U937 myelomonocytic leukemia cells. By focusing on the anti-apoptotic gene Bcl-2, the key regulator gene of granulocytic differentiation CCAAT/enhancer-binding protein α (CEBPA) and the tumor suppressor gene p14(ARF), we found that both AML1-ETO-expressing cell lines and t(8;21) leukemia samples displayed low levels of these three genes. Chromatin immunoprecipitation assays demonstrated that Bcl-2, CEBPA and p14(ARF) were direct transcriptional targets of AML1-ETO. The universal binding of AML1-ETO to genomic DNA resulted in recruitment of methyl-CpG binding protein 2 (MeCP2), reduction of histone H3 or H4 acetylation and increased trimethylation of histone H3 lysine 9 as well as lysine 27 indicating that AML1-ETO induced heterochromatic silencing of Bcl-2, CEBPA and p14(ARF). These results suggested that the aberrant transcription factor AML1-ETO epigenetically silenced the function of the Bcl-2, CEBPA and p14(ARF) genes by inducing repressed chromatin configurations at their promoters through histone modifications.
- Subjects :
- Cancer Research
Chromatin Immunoprecipitation
Oncogene Proteins, Fusion
Leukemia, Myelomonocytic, Acute
Histone H3
RUNX1 Translocation Partner 1 Protein
hemic and lymphatic diseases
Cell Line, Tumor
CEBPA
Tumor Suppressor Protein p14ARF
Humans
neoplasms
Transcription factor
Regulator gene
Cell Proliferation
biology
Promoter
Cell Differentiation
General Medicine
U937 Cells
Molecular biology
Chromatin
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
Histone
Oncology
Proto-Oncogene Proteins c-bcl-2
Core Binding Factor Alpha 2 Subunit
biology.protein
CCAAT-Enhancer-Binding Proteins
Chromatin immunoprecipitation
Subjects
Details
- ISSN :
- 17912431
- Volume :
- 30
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Oncology reports
- Accession number :
- edsair.doi.dedup.....fa91dac72af5da3228b7123b33b6c2d8