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Molecular and Cellular Biology, October 2001, p. 6470-6483, Vol. 21, No. 19
Department of
Biochemistry1 and Vanderbilt-Ingram
Cancer Center,2 Vanderbilt University School of
Medicine, Nashville, Tennessee 37232; Departments of
Pathology3 and Tumor Cell
Biology,4 St. Jude Children's Research
Hospital, Memphis, Tennessee 38105; and Department of
Biochemistry and Molecular Biology and the Feist-Weiller Cancer Center,
Louisiana State University Health Services Center, Shreveport,
Louisiana 71130-39325
Received 26 February 2001/Returned for modification 5 April
2001/Accepted 26 June 2001
t(8;21) and t(16;21) create two fusion proteins, AML-1-ETO and
AML-1-MTG16, respectively, which fuse the AML-1 DNA binding domain to
putative transcriptional corepressors, ETO and MTG16. Here, we show
that distinct domains of ETO contact the mSin3A and N-CoR corepressors
and define two binding sites within ETO for each of these corepressors.
In addition, of eight histone deacetylases (HDACs) tested, only the
class I HDACs HDAC-1, HDAC-2, and HDAC-3 bind ETO. However, these HDACs
bind ETO through different domains. We also show that the murine
homologue of MTG16, ETO-2, is also a transcriptional corepressor that
works through a similar but distinct mechanism. Like ETO, ETO-2
interacts with N-CoR, but ETO-2 fails to bind mSin3A. Furthermore,
ETO-2 binds HDAC-1, HDAC-2, and HDAC-3 but also interacts with HDAC-6
and HDAC-8. In addition, we show that expression of AML-1-ETO causes
disruption of the cell cycle in the G1 phase. Disruption of
the cell cycle required the ability of AML-1-ETO to repress
transcription because a mutant of AML-1-ETO,
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.19.6470-6483.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
ETO, a Target of t(8;21) in Acute Leukemia, Makes
Distinct Contacts with Multiple Histone Deacetylases and Binds
mSin3A through Its Oligomerization Domain

469, which removes the
majority of the corepressor binding sites, had no phenotype. Moreover,
treatment of AML-1-ETO-expressing cells with trichostatin A, an HDAC
inhibitor, restored cell cycle control. Thus, AML-1-ETO makes distinct
contacts with multiple HDACs and an HDAC inhibitor biologically
inactivates this fusion protein.
*
Corresponding author. Mailing address: Department of
Biochemistry, Vanderbilt University School of Medicine, 23rd and
Pierce, MRB II 512, Nashville, TN 37232. Phone: (615) 936-3582. Fax:
(615) 936-1790. E-mail:
scott.hiebert{at}mcmail.vanderbilt.edu.
Present address: Department of Biology, University of South
Carolina, Aiken, SC 29801.
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