The t(8;21) fusion protein contacts co-repressors and histone deacetylases to repress the transcription of the p14ARF tumor suppressor.
The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. The translocation fuses the DNA binding domain of AML1 to nearly all of the ETO co-repressor. ETO associates with the mSin3 and N-CoR co-repressors as well as histone deacetylases 1, 2, and 3. Although this is one of the most frequent chromosomal translocations in acute leukemia, accounting for 10-15% of the cases of acute myeloid leukemia (AML), the direct targets for transcriptional regulation that stimulate leukemogenesis are unknown. We found that AML1-ETO repressed the promoter of p14(ARF) tumor suppressor in transient transfection assays and reduced endogenous levels of p14(ARF) expression in multiple cell types. Chromatin immunoprecipitation assays demonstrated that AML1-ETO bound to the p14(ARF) promoter. In acute myeloid leukemia samples containing the t(8;21), levels of p14(ARF) mRNA were markedly lower when compared to other acute myeloid leukemias. Therefore, p14(ARF) is a direct transcriptional target of AML1-ETO.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. scott.hiebert@mcmai.vanderbilt.edu
Scott W
SW
Hiebert
Edward F
EF
Reed-Inderbitzin
Joseph
J
Amann
Brenda
B
Irvin
Kristie
K
Durst
Bryan
B
Linggi
D000208:Acute Disease; D017209:Apoptosis; D002455:Cell Division; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology; D009857:Oncogenes; D012097:Repressor Proteins / Q000235:genetics; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
D012097:Repressor Proteins; D025803:Tumor Suppressor Protein p14ARF; D006655:Histone Deacetylases