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

Bryan Linggi; Carsten Müller-Tidow; Louis van de Locht; Ming Hu; John Nip; Hubert Serve; Wolfgang E Berdel; Bert van der Reijden; Dawn E Quelle; Janet D Rowley; John Cleveland; Joop H Jansen; Pier Paolo Pandolfi; Scott W Hiebert

doi:10.1038/nm726

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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

Journal article

Peer reviewed

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

Bryan Linggi, Carsten Müller-Tidow, Louis van de Locht, Ming Hu, John Nip, Hubert Serve, Wolfgang E Berdel, Bert van der Reijden, Dawn E Quelle, Janet D Rowley, …

Nature medicine, Vol.8(7), pp.743-750

07/2002

DOI: 10.1038/nm726

PMID: 12091906

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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 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.

Plasmids

Translocation, Genetic

Oncogene Proteins, Fusion - metabolism

Humans

Gene Expression Regulation, Neoplastic

Hematopoietic Stem Cells - pathology

Chromosomes, Human, Pair 8

Transcription Factors - genetics

Antigens, CD - analysis

RUNX1 Translocation Partner 1 Protein

Transcription Factors - metabolism

Transcription, Genetic - physiology

Oncogene Proteins, Fusion - genetics

CD4 Antigens - analysis

Core Binding Factor Alpha 2 Subunit

K562 Cells

Tumor Cells, Cultured

Tumor Suppressor Protein p14ARF - genetics

Chromosomes, Human, Pair 21

Genes, Tumor Suppressor

Genes, Reporter

Repressor Proteins - metabolism

Leukemia, Myeloid, Acute - genetics

Details

Title: Subtitle: The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia
Creators: Bryan Linggi - Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Carsten Müller-Tidow
Louis van de Locht
Ming Hu
John Nip
Hubert Serve
Wolfgang E Berdel
Bert van der Reijden
Dawn E Quelle
Janet D Rowley
John Cleveland
Joop H Jansen
Pier Paolo Pandolfi
Scott W Hiebert
Resource Type: Journal article
Publication Details: Nature medicine, Vol.8(7), pp.743-750
Publisher: United States
DOI: 10.1038/nm726
PMID: 12091906
ISSN: 1078-8956
eISSN: 1546-170X
Grant note: R01-CA64140 / NCI NIH HHS R01-87549 / PHS HHS CA68485 / NCI NIH HHS R01-AG13726 / NIA NIH HHS
Language: English
Date published: 07/2002
Academic Unit: Pathology; Neuroscience and Pharmacology
Record Identifier: 9984040301002771

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