Topoisomerase II negatively modulates RAR function–a novel mechanism of retinoic acid resistance

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

^* To whom correspondence should be addressed. Email: wmiller{at}ldi.jgh.mcgill.ca.

	Abstract

Interactions between the retinoic acid receptor (RAR) and coregulators play a key role in coordinating gene transcription and myeloid differentiation. In acute promyelocytic leukemia (APL), RAR is fused with the promyelocytic leukemia gene resulting in the expression of a PML/RAR fusion protein t(15;17). Here, we report that Topoisomerase II beta (TopoII) associates with and negatively modulates RAR transcriptional activity, and increased levels and association of TopoII cause resistance to retinoic acid (RA) in APL cell lines. Knock down of TopoII was able to overcome resistance by permitting RA-induced differentiation and increased RA-gene expression. Overexpression of TopoII, 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 indicate that TopoII is bound to an RA-response element, and inhibition of TopoII causes hyper-acetylation 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 TopoII in gene regulation and differentiation.