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Molecular and Cellular Biology, January 2003, p. 607-619, Vol. 23, No. 2
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.2.607-619.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The inv(16) Fusion Protein Associates with Corepressors via a Smooth Muscle Myosin Heavy-Chain Domain

Kristie L. Durst,1 Bart Lutterbach,1,{dagger} Tanawan Kummalue,2 Alan D. Friedman,2 and Scott W. Hiebert1,3*

Department of Biochemistry,1 Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,3 Department of Oncology, Johns Hopkins University, Baltimore, Maryland 212312

Received 22 April 2002/ Returned for modification 6 June 2002/ Accepted 14 October 2002

Inversion(16) is one of the most frequent chromosomal translocations found in acute myeloid leukemia (AML), occurring in over 8% of AML cases. This translocation results in a protein product that fuses the first 165 amino acids of core binding factor ß to the coiled-coil region of a smooth muscle myosin heavy chain (CBFß/SMMHC). CBFß interacts with AML1 to form a heterodimer that binds DNA; this interaction increases the affinity of AML1 for DNA. The CBFß/SMMHC fusion protein cooperates with AML1 to repress the transcription of AML1-regulated genes. We show that CBFß/SMMHC contains a repression domain in the C-terminal 163 amino acids of the SMMHC region that is required for inv(16)-mediated transcriptional repression. This minimal repression domain is sufficient for the association of CBFß/SMMHC with the mSin3A corepressor. In addition, the inv(16) fusion protein specifically associates with histone deacetylase 8 (HDAC8). inv(16)-mediated repression is sensitive to HDAC inhibitors. We propose a model whereby the inv(16) fusion protein associates with AML1 to convert AML1 into a constitutive transcriptional repressor.

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

{dagger} Present address: Merck, Inc., West Point, Pa.

Molecular and Cellular Biology, January 2003, p. 607-619, Vol. 23, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.2.607-619.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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