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Molecular and Cellular Biology, May 1999, p. 3635-3644, Vol. 19, No. 5
Laboratory of Molecular Aspects of
Hematopoiesis1 and Division of
Hematologic Oncology,2 Department of Medicine,
Memorial Sloan-Kettering Cancer Center, New York, New York 10021
Received 23 June 1998/Returned for modification 18 August
1998/Accepted 19 February 1999
The AML1 and ETS families of transcription factors play critical
roles in hematopoiesis; AML1, and its non-DNA-binding heterodimer partner CBF
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Functional and Physical Interactions between AML1 Proteins and an
ETS Protein, MEF: Implications for the Pathogenesis of
t(8;21)-Positive Leukemias
, are essential for the development of definitive hematopoiesis in mice, whereas the absence of certain ETS proteins creates specific defects in lymphopoiesis or myelopoiesis. The promoter
activities of numerous genes expressed in hematopoietic cells are
regulated by AML1 proteins or ETS proteins. MEF (for myeloid ELF-1-like
factor) is a recently cloned ETS family member that, like AML1B, can
strongly transactivate several of these promoters, which led us to
examine whether MEF functionally or physically interacts with AML1
proteins. In this study, we demonstrate direct interactions between MEF
and AML1 proteins, including the AML1/ETO fusion protein, in
t(8;21)-positive acute myeloid leukemia (AML) cells. Using mutational
analysis, we identified a novel ETS-interacting subdomain (EID) in the
C-terminal portion of the Runt homology domain (RHD) in AML1 proteins
and determined that the N-terminal region of MEF was responsible for
its interaction with AML1. MEF and AML1B synergistically transactivated
an interleukin 3 promoter reporter gene construct, yet the activating
activity of MEF was abolished when MEF was coexpressed with AML1/ETO.
The repression by AML1/ETO was independent of DNA binding but depended on its ability to interact with MEF, suggesting that AML1/ETO can
repress genes not normally regulated by AML1 via protein-protein interactions. Interference with MEF function by AML1/ETO may lead to
dysregulation of genes important for myeloid differentiation, thereby
contributing to the pathogenesis of t(8;21) AML.
*
Corresponding author. Mailing address: Memorial
Sloan-Kettering Cancer Center, Box 575, 1275 York Ave., New York, NY
10021. Phone: (212) 639-7871. Fax: (212) 794-5849. E-mail:
s-nimer{at}mskcc.org.
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