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Molecular and Cellular Biology, December 1998, p. 7185-7191, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Aberrant Recruitment of the Nuclear Receptor Corepressor-Histone Deacetylase Complex by the Acute Myeloid Leukemia Fusion Partner ETO

Vania Gelmetti,1 Jinsong Zhang,2 Mirco Fanelli,1 Saverio Minucci,1,* Pier Giuseppe Pelicci,1,* and Mitchell A. Lazar2,*

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and Departments of Genetics and Biochemistry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,2 and Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy1

Received 1 July 1998/Returned for modification 18 August 1998/Accepted 3 September 1998

Nuclear receptor corepressor (CoR)-histone deacetylase (HDAC) complex recruitment is indispensable for the biological activities of the retinoic acid receptor fusion proteins of acute promyelocytic leukemias. We report here that ETO (eight-twenty-one or MTG8), which is fused to the acute myelogenous leukemia 1 (AML1) transcription factor in t(8;21) AML, interacts via its zinc finger region with a conserved domain of the corepressors N-CoR and SMRT and recruits HDAC in vivo. The fusion protein AML1-ETO retains the ability of ETO to form stable complexes with N-CoR/SMRT and HDAC. Deletion of the ETO C terminus abolishes CoR binding and HDAC recruitment and severely impairs the ability of AML1-ETO to inhibit differentiation of hematopoietic precursors. These data indicate that formation of a stable complex with CoR-HDAC is crucial to the activation of the leukemogenic potential of AML1 by ETO and suggest that aberrant recruitment of corepressor complexes is a general mechanism of leukemogenesis.

* Corresponding author. Mailing address for Saverio Minucci: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy. Phone: 39-2-57489869. Fax: 39-2-54489851. E-mail: sminucci{at}ieo.cilea.it. Mailing address for Pier Giuseppe Pelicci: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy. Phone: 39-2-57489869. Fax: 39-2-54489851. E-mail: pgpelicci{at}ieo.cilea.it. Mailing address for Mitchell A. Lazar: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Phone: (215) 898-0210. Fax: (215) 898-5408. E-mail: lazar{at}mail.med.upenn.edu.

Molecular and Cellular Biology, December 1998, p. 7185-7191, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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