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Mol Cell Biol, June 1998, p. 3604-3611, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The MYND Motif Is Required for Repression of Basal Transcription from the Multidrug Resistance 1 Promoter by the t(8;21) Fusion Protein

Bart Lutterbach,1 Daxi Sun,2 John Schuetz,2 and Scott W. Hiebert1,*

Department of Biochemistry and the Vanderbilt Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37027,1 and Department of Pharmaceutical Science, St. Jude Children's Research Hospital, Memphis, Tennessee 381052

Received 2 December 1997/Returned for modification 20 February 1998/Accepted 24 March 1998

Chromosomal translocations in acute leukemia that affect the AML-1/CBFbeta transcription factor complex create dominant inhibitory proteins. However, the mechanisms by which these proteins act remain obscure. Here we demonstrate that the multidrug resistance 1 (MDR-1) promoter is a target for AML/ETO transcriptional repression. This repression is of basal, not activated, expression from the MDR-1 promoter and thus represents a new mechanism for AML/ETO function. We have defined two domains in AML/ETO that are required for repression of basal transcription from the MDR-1 promoter: a hydrophobic heptad repeat (HHR) motif and a conserved zinc finger (ZnF) domain termed the MYND domain. The HHR mediates formation of AML/ETO homodimers and AML/ETO-ETO heterodimers. Single serine substitutions at conserved cysteine residues within the predicted ZnFs also abrogate transcriptional repression. Finally, we observe that AML/ETO can also inhibit Ets-1 activation of the MDR-1 promoter, indicating that AML/ETO can disrupt both basal and Ets-1-dependent transcription. The fortuitous inhibition of MDR-1 expression in t(8;21)-containing leukemias may contribute to the favorable response of these patients to chemotherapeutic drugs.

* Corresponding author. Mailing address: Department of Biochemistry and the Vanderbilt Cancer Center, Vanderbilt University School of Medicine, 21st and Garland, Nashville, TN 37027. Phone: (615) 936-3582. Fax: (615) 936-1790. E-mail: scott.hiebert{at}mcmail.vanderbilt.edu.

Mol Cell Biol, June 1998, p. 3604-3611, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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