Downregulation of topoisomerase IIβ in myeloid leukemia cell lines leads to activation of apoptosis following all-trans retinoic acid-induced differentiation/growth arrest

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