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  • Original Paper
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Expression of NPM-RARα fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis

Oncogene volume 22, pages 6424–6435 (2003)Cite this article

Abstract

We have investigated the effects of acute promyelocytic leukemia (APL) fusion gene NPM-RARα on the function of PPARγ using the monoblastic cell line U937. U937 cells were transduced using a retrovirus carrying NPM-RARα. While treatment with the synthetic PPARγ ligand troglitazone (TG) had no effect on the viability of U937 cells, TG treatment of U937/NPM-RARα cells resulted in a dramatic decrease in cell viability, dependent upon both the concentration of TG and the level of expression of NPM-RARα. Analysis of the cell cycle profile and flow cytometry with annexin V confirmed that these effects of TG were due to induction of apoptosis. Induction of apoptosis was accompanied by caspase-8 and caspase-9 activation, and could be blocked by treatment with the caspase inhibitor Z-VAD-FMK. Cotreatment of U937/NPM-RARα cells with all-trans retinoic acid (atRA) abrogated the induction of apoptosis by TG. Induction of apoptosis was seen also in the PML-RARα-expressing APL cell line NB4, and in several other atRA-sensitive leukemia cell lines, demonstrating that this effect is limited neither to the monocyte lineage nor to the rare NPM-RARα fusion variant. RXRα/NPM-RARα heterodimers were found to interact directly with a PPARγ-responsive element in vitro. We conclude that in the presence of X-RARα, TG induces cell death due to apoptosis via the caspase pathway. These observations suggest the investigation of PPARγ ligands as therapeutic agents in acute leukemia.

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Acknowledgements

This work was supported by funds from The National Cancer Institute of Canada (SK-R, 013087), The Canadian Institutes of Health Research (SK-R, MOP36504); RAW was supported by a Canadian Institutes of Health Research Clinician-Scientist Phase II award (MC2-55544).

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Authors and Affiliations

  1. The Department of Cellular and Molecular Biology, The Ontario Cancer Institute, The University Health Network, Toronto, M5G-2M9, Ontario, Canada

    Suzanne Kamel-Reid, Tong Zhang & Richard A Wells

  2. The Department of Laboratory Medicine and Pathobiology, The Institute of Medical Sciences, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Suzanne Kamel-Reid

  3. The Department of Medicine, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Richard A Wells

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  1. Suzanne Kamel-Reid
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Correspondence to Richard A Wells.

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Kamel-Reid, S., Zhang, T. & Wells, R. Expression of NPM-RARα fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis. Oncogene 22, 6424–6435 (2003). https://doi.org/10.1038/sj.onc.1206696

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