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Molecular and Cellular Biology, March 2008, p. 2066-2077, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.01576-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Topoisomerase IIβ Negatively Modulates Retinoic Acid Receptor {alpha} Function: a Novel Mechanism of Retinoic Acid Resistance{triangledown}

Suzan McNamara, Hongling Wang, Nessrine Hanna, and Wilson H. Miller Jr.*

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital Segal Cancer Center, and McGill University Department of Oncology, Montreal, Quebec, Canada

Received 27 August 2007/ Returned for modification 4 October 2007/ Accepted 8 January 2008

Interactions between retinoic acid (RA) receptor {alpha} (RAR{alpha}) and coregulators play a key role in coordinating gene transcription and myeloid differentiation. In patients with acute promyelocytic leukemia (APL), the RAR{alpha} gene is fused with the promyelocytic leukemia (PML) gene via the t(15;17) translocation, resulting in the expression of a PML/RAR{alpha} fusion protein. Here, we report that topoisomerase II beta (TopoIIβ) associates with and negatively modulates RAR{alpha} transcriptional activity and that increased levels of and association with TopoIIβ cause resistance to RA in APL cell lines. Knockdown of TopoIIβ was able to overcome resistance by permitting RA-induced differentiation and increased RA gene expression. Overexpression of TopoIIβ in clones from an RA-sensitive cell line conferred resistance by a reduction in RA-induced expression of target genes and differentiation. Chromatin immunoprecipitation assays indicated that TopoIIβ is bound to an RA response element and that inhibition of TopoIIβ causes hyperacetylation of histone 3 at lysine 9 and activation of transcription. Our results identify a novel mechanism of resistance in APL and provide further insight to the role of TopoIIβ in gene regulation and differentiation.

* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Segal Cancer Center, 3755 Chemin de la Côte-Ste-Catherine, Montreal, Quebec, Canada H3T 1E2. Phone: (514) 340-8260. Fax: (514) 340-7576. E-mail: wmiller{at}ldi.jgh.mcgill.ca

{triangledown} Published ahead of print on 22 January 2008.

Molecular and Cellular Biology, March 2008, p. 2066-2077, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.01576-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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