Abstract
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 p14ARF tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1–ETO. AML1–ETO repressed the p14ARF promoter and reduced endogenous levels of p14ARF expression in multiple cell types. In contrast, AML1 stimulated p14ARF expression and induced phenotypes consistent with cellular senescence. Chromatin immunoprecipitation assays demonstrated that AML1–ETO was specifically bound to the p14ARF promoter. In acute myeloid leukemia samples containing the t(8;21), levels of p14ARF mRNA were markedly lower when compared with other acute myeloid leukemias lacking this translocation. Repression of p14ARF may explain why p53 is not mutated in t(8;21)-containing leukemias and suggests that p14ARF is an important tumor suppressor in a large number of human leukemias.
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Acknowledgements
We thank P. Jones and K. Robertson (NIH) for providing the p14ARF promoter plasmid; S. Nimer for the Kasumi-1 cells; A. Melnick for SKNO-1 cells; K.S. Luce, Y. Hou and D. King for technical assistance; and the Vanderbilt-Ingram Cancer Center sequencing facility. This work was supported by NIH grants RO1-AG13726, RO1-CA64140 and RO1-87549, a Center grant from the National Cancer Institute (CA68485), and the Vanderbilt-Ingram Cancer Center. The laboratories of C.M.-T. and H. S. are supported by grants from the IZKF at the University of Munster, the Deutsche Forschungsgemeinschaft and the José-Carreras Leukemia Foundation. J.N. was a Leukemia Society of America Special Fellow (Grant No. 3827-99).
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Linggi, B., Müller-Tidow, C., van de Locht, L. et al. The t(8;21) fusion protein, AML1–ETO, specifically represses the transcription of the p14ARF tumor suppressor in acute myeloid leukemia. Nat Med 8, 743–750 (2002). https://doi.org/10.1038/nm726
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DOI: https://doi.org/10.1038/nm726
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