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The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia.

Linggi B, Müller-Tidow C, van de Locht L, Hu M, Nip J, Serve H, Berdel WE, van der Reijden B, Quelle DE, Rowley JD, Cleveland J, Jansen JH, Pandolfi PP, Hiebert SW
Nat Med. 2002 8 (7): 743-50

PMID: 12091906 · DOI:10.1038/nm726

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.

MeSH Terms (21)

Antigens, CD CD4 Antigens Chromosomes, Human, Pair 8 Chromosomes, Human, Pair 21 Core Binding Factor Alpha 2 Subunit Gene Expression Regulation, Neoplastic Genes, Reporter Genes, Tumor Suppressor Hematopoietic Stem Cells Humans K562 Cells Leukemia, Myeloid, Acute Oncogene Proteins, Fusion Plasmids Repressor Proteins RUNX1 Translocation Partner 1 Protein Transcription, Genetic Transcription Factors Translocation, Genetic Tumor Cells, Cultured Tumor Suppressor Protein p14ARF

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