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Acute Leukemias

Targeting PKCδ-mediated topoisomerase IIβ overexpression subverts the differentiation block in a retinoic acid-resistant APL cell line

Leukemia volume 24, pages 729–739 (2010)Cite this article

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Abstract

Retinoic acid (RA) relieves the maturation block in t(15:17) acute promyelocytic leukemia (APL), leading to granulocytic differentiation. However, RA treatment alone invariably results in RA resistance, both in vivo and in vitro. RA-resistant cell lines have been shown to serve as useful models for elucidation of mechanisms of resistance. Previously, we identified topoisomerase II beta (TOP2B) as a novel mediator of RA-resistance in APL cell lines. In this study, we show that both TOP2B protein stability and activity are regulated by a member of the protein kinase C (PRKC) family, PRKC delta (PRKCD). Co-treatment with a pharmacologic inhibitor of PRKCD and RA resulted in the induction of an RA responsive reporter construct, as well as the endogenous RA target genes, CEBPE, CYP26A1 and RIG-I. Furthermore, the co-treatment overcame the differentiation block in RA-resistant cells, as assessed by morphological analysis, restoration of promyelocytic leukemia nuclear bodies, induction of CD11c cell surface expression and an increase in nitro-blue-tetrazolium reduction. Cumulatively, our data suggest a model whereby inhibition of PRKCD decreases TOP2B protein levels, leading to a loss of TOP2B-mediated repressive effects on RA-induced transcription and granulocytic differentiation.

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Acknowledgements

We are grateful to Björn D Kuhl and Filippa Pettersson for critical reading of the paper. This work was supported by a grant from the Canadian Institutes of Health Research. WH Miller, Jr, is a Chercheur National of Fonds de la Recherche en Santé du Québec. J Nichol was supported by a student fellowship from the Cole Foundation.

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  1. S McNamara and J N Nichol: These authors contributed equally to this work.

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  1. Division of Experimental Medicine, Department of Oncology, Segal Cancer Comprehensive Centre, Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, McGill University, Montréal, Quebec, Canada

    S McNamara, J N Nichol & W H Miller Jr

  2. Segal Cancer Comprehensive Centre, Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, Montréal, Quebec, Canada

    H Wang

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McNamara, S., Nichol, J., Wang, H. et al. Targeting PKCδ-mediated topoisomerase IIβ overexpression subverts the differentiation block in a retinoic acid-resistant APL cell line. Leukemia 24, 729–739 (2010). https://doi.org/10.1038/leu.2010.27

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