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Retinoic acid, but not arsenic trioxide, degrades the PLZF/RARα fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient

Oncogene volume 18, pages 1113–1118 (1999)Cite this article

Abstract

Primary blasts of a t(11;17)(q23;q21) acute promyelocytic leukaemia (APL) patient were analysed with respect to retinoic acid (RA) and arsenic trioxide (As2O3) sensitivity as well as PLZF/RARα status. Although RA induced partial monocytic differentiation ex vivo, but not in vivo, As203 failed to induce apoptosis in culture, contrasting with t(15;17) APL and arguing against the clinical use of As203 in t(11;17)(q23;q21) APL. Prior to cell culture, PLZF/RARα was found to exactly co-localize with PML onto PML nuclear bodies. However upon cell culture, it quickly shifted towards microspeckles, its localization found in transfection experiments. Arsenic trioxide, known to induce aggregation of PML nuclear bodies, left the microspeckled PLZF/RARα localization completely unaffected. RA treatment led to PLZF/RARα degradation. However, this complete PLZF/RARα degradation was not accompanied by differentiation or apoptosis, which could suggest a contribution of the reciprocal RARα/PLZF fusion product in leukaemogenesis or the existence of irreversible changes induced by the chimera.

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Acknowledgements

We thank the LPH for their help with photography, and Michel Schmid and Christel Doliger for their excellent confocal microscopy analysis. Drs P Chambon and B Allegretto are thanked for the kind gift of antibodies. All members of the PML group are acknowledged for stimulating discussions and critical reading of the manuscript. M Gianni was supported by a grant from the `Ligue Nationale contre le Cancer' and FRM.

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Authors and Affiliations

  1. CNRS UPR90-51, laboratoire associé au comité de Paris de la Ligue contre le Cancer, Hôpital St. Louis, 1 Av. Claude Vellefaux, 75010, France

    Marcel HM Koken, Maurizio Gianni & Hugues de Thé

  2. Service Clinique des Maladies du Sang, Hôpital St. Louis, France

    Marie-Thérèse Daniel

  3. Service d' Hématologie, Hôpital Necker, France

    Agnes Buzyn & Bruno Varet

  4. Service de Medicine Interne, Hôpital de Moulins, Moulins, France

    Patricia Minard

  5. Service d'Hématologie, Hôpital St. Louis, Paris, France

    Laurent Degos

  6. Chester Beatty Laboratories, London

    Arthur Zelent

  7. Mount Sinaï Medical Center, New York, USA

    Jonathan Licht

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Koken, M., Daniel, MT., Gianni, M. et al. Retinoic acid, but not arsenic trioxide, degrades the PLZF/RARα fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient. Oncogene 18, 1113–1118 (1999). https://doi.org/10.1038/sj.onc.1202414

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