1. ¹Experimental Therapeutics Program, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH, USA
2. ²College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
3. ³Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
4. ⁴Department of Internal Medicine II, Okayama University Medical School, Okayama, Japan

Correspondence: Dr R Ganapathi, Taussig Cancer Center R40, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. E-mail: ganapar@ccf.org

Received 22 December 2005; Revised 15 June 2006; Accepted 21 June 2006; Published online 17 August 2006.

Abstract

Among the topoisomerase (topo) II isozymes ( and ), topo II has been suggested to regulate differentiation. In this study, we examined the role of topo II in all-trans retinoic acid (ATRA)-induced differentiation of myeloid leukemia cell lines. Inhibition of topo II activity or downregulation of protein expression enhanced ATRA-induced differentiation/growth arrest and apoptosis. ATRA-induced apoptosis in topo II-deficient cells involved activation of the caspase cascade and was rescued by ectopic expression of topo II. Gene expression profiling led to the identification of peroxiredoxin 2 (PRDX2) as a candidate gene that was downregulated in topo II-deficient cells. Reduced expression of PRDX2 validated at the mRNA and protein level, in topo II-deficient cells correlated with increased accumulation of reactive oxygen species (ROS) following ATRA-induced differentiation. Overexpression of PRDX2 in topo II-deficient cells led to reduced accumulation of ROS and partially reversed ATRA-induced apoptosis. These results support a role for topo II in survival of ATRA-differentiated myeloid leukemia cells. Reduced expression of topo II induces apoptosis in part by impairing the anti-oxidant capacity of the cell owing to downregulation of PRDX2. Thus, suppression of topo II and/or PRDX2 levels in myeloid leukemia cells provides a novel approach for improving ATRA-based differentiation therapy.