Inhibition of the transforming growth factor beta 1 signaling pathway by the AML1/ETO leukemia-associated fusion protein.
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 beta1 (TGF-beta1) 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-beta1. 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-beta1 in stimulating reporter gene activity, whereas AML1/ETO represses basal promoter activity and blocks the response to TGF-beta1. Considering the critical role of TGF-beta1 in the growth and differentiation of hematopoietic cells, interference with TGF-beta1 signaling by AML1/ETO may contribute to leukemogenesis.
Jakubowiak
A
A
Laboratory of Molecular Aspects of Hematopoiesis, Division of Hematologic Oncology, and Department of Medicine and the Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Pouponnot
C
C
Berguido
F
F
Frank
R
R
Mao
S
S
Massague
J
J
Nimer
S D
SD
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D000075142:RUNX1 Translocation Partner 1 Protein; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta