The t(8;21) fusion protein contacts co-repressors and histone deacetylases to repress the transcription of the p14 ARF tumor suppressor

Abstract

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.