The t(8;21) fusion protein, AML1?ETO, specifically represses the transcription of the p14ARF tumor suppressor in acute myeloid leukemia.

The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. This translocation creates a fusion protein consisting of the acute myeloid leukemia-1 transcription factor and the eight-twenty-one corepressor (AML1?ETO), which represses transcription through AML1 (RUNX1) DNA binding sites and immortalizes hematopoietic progenitor cells. We have identified the p14^ARF tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1?ETO. AML1?ETO repressed the p14^ARF promoter and reduced endogenous levels of p14^ARF expression in multiple cell types. In contrast, AML1 stimulated p14^ARF expression and induced phenotypes consistent with cellular senescence. Chromatin immunoprecipitation assays demonstrated that AML1?ETO was specifically 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 with other acute myeloid leukemias lacking this translocation. Repression of p14^ARF may explain why p53 is not mutated in t(8;21)-containing leukemias and suggests that p14^ARF is an important tumor suppressor in a large number of human leukemias. [ABSTRACT FROM AUTHOR]