ETO, a Target of t(8;21) in Acute Leukemia, Makes Distinct Contacts with Multiple Histone Deacetylases and Binds mSin3A through Its Oligomerization Domain

doi:10.1128/MCB.21.19.6470-6483.2001

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Molecular and Cellular Biology, October 2001, p. 6470-6483, Vol. 21, No. 19
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

Joseph M. Amann,¹^,² John Nip,¹^,² David K. Strom,¹^,²^, Bart Lutterbach,¹^,² Hironori Harada,³ Noel Lenny,³^,⁴ James R. Downing,³ Shari Meyers,⁵ and Scott W. Hiebert¹^,²^,^*

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 bindingdomain to putative transcriptional corepressors, ETO and MTG16.Here, we show that distinct domains of ETO contact the mSin3Aand N-CoR corepressors and define two binding sites within ETOfor each of these corepressors. In addition, of eight histonedeacetylases (HDACs) tested, only the class I HDACs HDAC-1, HDAC-2,and HDAC-3 bind ETO. However, these HDACs bind ETO through differentdomains. We also show that the murine homologue of MTG16, ETO-2,is also a transcriptional corepressor that works through a similarbut 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 disruptionof the cell cycle in the G₁ phase. Disruption of the cell cyclerequired the ability of AML-1-ETO to repress transcription becausea mutant of AML-1-ETO, $Delta$ 469, which removes the majority of thecorepressor binding sites, had no phenotype. Moreover, treatmentof AML-1-ETO-expressing cells with trichostatin A, an HDAC inhibitor,restored cell cycle control. Thus, AML-1-ETO makes distinct contactswith multiple HDACs and an HDAC inhibitor biologically inactivatesthis fusionprotein.

^* 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, SC29801.

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