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Differentiation

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

Leukemia volume 20, pages 1809–1818 (2006)Cite this article

Abstract

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

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Acknowledgements

This work was supported by USPHS Grants RO1 CA74939, RO1 DK56917 and RO1 CA117928. Eli Zarkhin was supported by a Joseph S Silber Student Fellowship, American Cancer Society, Cuyahoga County Unit. We thank Dr R Gallagher, Albert Einstein College of Medicine, Bronx, New York for generously providing the AP-1060 cells; Dr J Maciejewski, Cleveland Clinic Foundation, Cleveland, Ohio for generously providing the KG1 cells; and Dr I Hickson for the generous gift of topo IIα antibody. We gratefully acknowledge Terri O'Brian and Jim Reed of the Art-Medical Illustrations and Photography department for skillful preparation of the artwork.

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Authors and Affiliations

  1. Experimental Therapeutics Program, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH, USA

    K Chikamori, J E Hill, D R Grabowski, E Zarkhin, A G Grozav, S A J Vaziri, L R Rybicki, R M Bukowski, M K Ganapathi & R Ganapathi

  2. College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

    J Wang & A Yen

  3. Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    A V Gudkov

  4. Department of Internal Medicine II, Okayama University Medical School, Okayama, Japan

    M Tanimoto

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  1. K Chikamori
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  2. J E Hill
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  9. L R Rybicki
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Correspondence to R Ganapathi.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Chikamori, K., Hill, J., Grabowski, D. et al. Downregulation of topoisomerase IIβ in myeloid leukemia cell lines leads to activation of apoptosis following all-trans retinoic acid-induced differentiation/growth arrest. Leukemia 20, 1809–1818 (2006). https://doi.org/10.1038/sj.leu.2404351

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