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Molecular and Cellular Biology, December 1998, p. 7176-7184, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

ETO, a Target of t(8;21) in Acute Leukemia, Interacts with the N-CoR and mSin3 Corepressors

Bart Lutterbach,1,2 Jennifer J. Westendorf,1,2 Bryan Linggi,1,2 Andrea Patten,1,2 Mariko Moniwa,3 James R. Davie,3 Khanh D. Huynh,4 Vivian J. Bardwell,4,5 Robert M. Lavinsky,6 Michael G. Rosenfeld,6,7 Christopher Glass,7 Edward Seto,8 and Scott W. Hiebert1,2,*

Department of Biochemistry1 and Vanderbilt Cancer Center,2 Vanderbilt University School of Medicine, Nashville, Tennessee 37232; Department of Biochemistry and Molecular Biology, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada3; Biochemistry, Molecular Biology and Biophysics Graduate Program4 and Department of Biochemistry, Institute of Human Genetics and Cancer Center,5 University of Minnesota, Minneapolis, Minnesota 55455; Howard Hughes Medical Institute6 and Department of Medicine, School of Medicine,7 University of California, San Diego, La Jolla, California 92093-0648; and H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 336128

Received 16 July 1998/Returned for modification 18 August 1998/Accepted 27 August 1998

t(8;21) is one of the most frequent translocations associated with acute myeloid leukemia. It produces a chimeric protein, acute myeloid leukemia-1 (AML-1)-eight-twenty-one (ETO), that contains the amino-terminal DNA binding domain of the AML-1 transcriptional regulator fused to nearly all of ETO. Here we demonstrate that ETO interacts with the nuclear receptor corepressor N-CoR, the mSin3 corepressors, and histone deacetylases. Endogenous ETO also cosediments on sucrose gradients with mSin3A, N-CoR, and histone deacetylases, suggesting that it is a component of one or more corepressor complexes. Deletion mutagenesis indicates that ETO interacts with mSin3A independently of its association with N-CoR. Single amino acid mutations that impair the ability of ETO to interact with the central portion of N-CoR affect the ability of the t(8;21) fusion protein to repress transcription. Finally, AML-1/ETO associates with histone deacetylase activity and a histone deacetylase inhibitor impairs the ability of the fusion protein to repress transcription. Thus, t(8;21) fuses a component of a corepressor complex to AML-1 to repress transcription.


* Corresponding author. Mailing address: Department of Biochemistry, Vanderbilt Cancer Center, Vanderbilt University School of Medicine, Medical Research Building II, Rm. 512, 23rd and Pierce, Nashville, TN 37232. Phone: (615) 936-3582. Fax: (615) 936-1790. E-mail: scott.hiebert{at}mcmail.vanderbilt.edu.


Molecular and Cellular Biology, December 1998, p. 7176-7184, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.



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