The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) 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.
Linggi
Bryan
B
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Müller-Tidow
Carsten
C
van de Locht
Louis
L
Hu
Ming
M
Nip
John
J
Serve
Hubert
H
Berdel
Wolfgang E
WE
van der Reijden
Bert
B
Quelle
Dawn E
DE
Rowley
Janet D
JD
Cleveland
John
J
Jansen
Joop H
JH
Pandolfi
Pier Paolo
PP
Hiebert
Scott W
SW
D015703:Antigens, CD / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
C107844:AML1-ETO fusion protein, human; D015703:Antigens, CD; D015704:CD4 Antigens; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF