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Molecular and Cellular Biology, March 2000, p. 2075-2086, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The ETO Protein Disrupted in t(8;21)-Associated Acute Myeloid Leukemia Is a Corepressor for the Promyelocytic Leukemia Zinc Finger Protein

Ari M. Melnick,1 Jennifer J. Westendorf,2 Adam Polinger,3 Graeme W. Carlile,3 Sally Arai,1,4 Helen J. Ball,3 Bart Lutterbach,2 Scott W. Hiebert,2 and Jonathan D. Licht1,3,5,*

Department of Medicine,1 The Derald H. Ruttenberg Cancer Center,3 and Department of Biochemistry and Molecular Biology,5 Mount Sinai School of Medicine, New York, New York 10029; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 372322; and Oncology Center, Johns Hopkins University, Baltimore, Maryland 212184

Received 27 October 1999/Returned for modification 23 November 1999/Accepted 20 December 1999

The ETO protein was originally identified by its fusion to the AML-1 transcription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1-ETO fusion is an aberrant transcriptional regulator due to the ability of ETO, which does not bind DNA itself, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A and histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor alpha  in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found that ETO is one of the corepressors recruited by PLZF. The PLZF and ETO proteins associate in vivo and in vitro, and ETO can potentiate transcriptional repression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by PLZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a sequence-specific transcription factor and indicates that, like other corepressors, it functions through the action of histone deactylase.

* Corresponding author. Mailing address: Box 1130, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Phone: (212) 659-5487. Fax: (212) 849-2523. E-mail: jonathan.licht{at}mssm.edu.

Molecular and Cellular Biology, March 2000, p. 2075-2086, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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