Inhibition of the transforming growth factor β1 signaling pathway by the AML1/ETO leukemia-associated fusion protein

Andrzej Jakubowiak, Celio Pouponnot, Francisco Berguido, Richard Frank, Shifeng Mao, Joan Massagué, Stephen D Nimer

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Abstract

The t(8;21) translocation, found in adult acute myelogenous leukemia, results in the formation of an AML1/ETO chimeric transcription factor. AML1/ETO expression leads to alterations in hematopoietic progenitor cell differentiation, although its role in leukemic transformation is not clear. The N-terminal portion of AML1, which is retained in AML1/ETO, contains a region of homology to the FAST proteins, which cooperate with Smads to regulate transforming growth factor β1 (TGF-β1) target genes. We have demonstrated the physical association of Smad proteins with AML1 and AML1/ETO by immunoprecipitation and have mapped the region of interaction to the runt homology domain in these AML1 proteins. Using confocal microscopy, we demonstrated that AML1, and ETO and/or AML1/ETO, colocalize with Smads in the nucleus of t(8;21)-positive Kasumi-1 cells, in the presence but not the absence of TGF-β1. Using transient transfection assays and a reporter gene construct that contains both Smad and AML1 consensus binding sequences, we demonstrated that overexpression of AML1B cooperates with TGF-β1 in stimulating reporter gene activity, whereas AML1/ETO represses basal promoter activity and blocks the response to TGF-β1. Considering the critical role of TGF-β1 in the growth and differentiation of hematopoietic cells, interference with TGF-β1 signaling by AML1/ETO may contribute to leukemogenesis.

Original languageEnglish
Pages (from-to)40282-40287
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number51
DOIs
StatePublished - Dec 22 2000
Externally publishedYes

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Transforming Growth Factors
Leukemia
Fusion reactions
Proteins
Genes
Reporter Genes
Cell Differentiation
Smad Proteins
Confocal microscopy
Consensus Sequence
Hematopoietic Stem Cells
Immunoprecipitation
Acute Myeloid Leukemia
Confocal Microscopy
Transfection
Assays
Transcription Factors
Cells
Association reactions
Growth

ASJC Scopus subject areas

  • Biochemistry

Cite this

Inhibition of the transforming growth factor β1 signaling pathway by the AML1/ETO leukemia-associated fusion protein. / Jakubowiak, Andrzej; Pouponnot, Celio; Berguido, Francisco; Frank, Richard; Mao, Shifeng; Massagué, Joan; Nimer, Stephen D.

In: Journal of Biological Chemistry, Vol. 275, No. 51, 22.12.2000, p. 40282-40287.

Research output: Contribution to journalArticle

Jakubowiak, Andrzej ; Pouponnot, Celio ; Berguido, Francisco ; Frank, Richard ; Mao, Shifeng ; Massagué, Joan ; Nimer, Stephen D. / Inhibition of the transforming growth factor β1 signaling pathway by the AML1/ETO leukemia-associated fusion protein. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 51. pp. 40282-40287.
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