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.

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.
AuthorsWen-Yue Zhuang, Jian-Nong Cen, Yun Zhao, Zi-Xing Chen
JournalOncology reports (Oncol Rep) Vol. 30 Issue 1 Pg. 185-92 (Jul 2013) ISSN: 1791-2431 [Electronic] Greece
PMID23673926 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • AML1-ETO fusion protein, human
  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p14ARF
  • CCAAT-Enhancer-Binding Proteins (genetics)
  • Cell Differentiation (genetics)
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin Immunoprecipitation
  • Core Binding Factor Alpha 2 Subunit (metabolism)
  • DNA-Binding Proteins (metabolism)
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Leukemia, Myelomonocytic, Acute (genetics, metabolism)
  • Oncogene Proteins, Fusion (metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (genetics)
  • Tumor Suppressor Protein p14ARF (genetics)
  • U937 Cells

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