Topoisomerase IIβ negatively modulates retinoic acid receptor α function:: a novel mechanism of retinoic acid resistance

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 (TopoII beta) associates with and negatively modulates RAR alpha transcriptional activity and that increased levels of and association with TopoII beta cause resistance to RA in APL cell lines. Knockdown of TopoII beta was able to overcome resistance by permitting RA-induced differentiation and increased RA gene expression. Overexpression of TopoII beta 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 TopoII beta is bound to an RA response element and that inhibition of TopoII beta 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 TopoII beta in gene regulation and differentiation.