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Retinoids Biology

The role of RAR and RXR activation in retinoid-induced tissue factor suppression

Leukemia volume 14, pages 1105–1111 (2000)Cite this article

Abstract

Excessive expression of tissue factor (TF) is a common finding in leukaemic cells and may contribute to thrombotic complications in patients. Retinoic acid has been shown to induce differentiation and reduce TF expression in acute promyelocytic leukaemia (APL) cells in vitro, and to induce remission in APL patients. Treatment of the APL cell line NB4 with the specific retinoic acid receptor-α (RARα) agonists Ro40–6055 or TTNPB resulted in down-regulation of TF expression and in induction of differentiation. The activation of RARβ, RARγ or retinoid X receptor (RXR) did not suppress the constitutive TF expression in NB4 cells. Moreover, the RARα antagonist Ro41-5253 blocked the retinoid-induced down-regulation of TF. In contrast, in the monoblastic U-937 cell line only a partial suppression of TF antigen expression and activity was observed by treatment with the RAR agonist TTNPB or the RXR agonist SR11237 alone. However, the combination of TTNPB and SR11237 resulted in a pronounced down-regulation of TF expression and induction of differentiation in U-937 cells. We show for the first time that the activation of both subunits of the RARα-RXR transcriptional complex is needed for TF suppression in U-937 cells, whereas in NB4 cells RARα activation alone is sufficient. Thus, distinct molecular mechanisms for TF suppression seem to be operating in leukaemic cell lines of different origin.

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Acknowledgements

This study was supported by the Swedish Cancer Society. We thank Michael Klaus (Hoffmann-La Roche, Basel, Switzerland) for providing us the nuclear receptor ligands and Inger Karlberg for skilful technical assistance.

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Authors and Affiliations

  1. Department of Medical Sciences, Uppsala University, Uppsala, S-751 85, Sweden

    T Tenno, S Jossan & A Siegbahn

  2. Department of Genetics and Pathology, Uppsala University, Uppsala, S-751 85, Sweden

    J Botling, F Öberg & K Nilsson

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Tenno, T., Botling, J., Öberg, F. et al. The role of RAR and RXR activation in retinoid-induced tissue factor suppression. Leukemia 14, 1105–1111 (2000). https://doi.org/10.1038/sj.leu.2401785

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