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Activation of a promyelocytic leukemia–tumor protein 53 axis underlies acute promyelocytic leukemia cure

Nature Medicine volume 20, pages 167174 (2014) | Download Citation

Abstract

Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)–retinoic acid receptor-α (PML-RARA) fusion protein, which interferes with nuclear receptor signaling and PML nuclear body (NB) assembly. APL is the only malignancy definitively cured by targeted therapies: retinoic acid (RA) and/or arsenic trioxide, which both trigger PML-RARA degradation through nonoverlapping pathways. Yet, the cellular and molecular determinants of treatment efficacy remain disputed. We demonstrate that a functional Pml–transformation-related protein 53 (Trp53) axis is required to eradicate leukemia-initiating cells in a mouse model of APL. Upon RA-induced PML-RARA degradation, normal Pml elicits NB reformation and induces a Trp53 response exhibiting features of senescence but not apoptosis, ultimately abrogating APL-initiating activity. Apart from triggering PML-RARA degradation, arsenic trioxide also targets normal PML to enhance NB reformation, which may explain its clinical potency, alone or with RA. This Pml-Trp53 checkpoint initiated by therapy-triggered NB restoration is specific for PML-RARA–driven APL, but not the RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARA variant. Yet, as NB biogenesis is druggable, it could be therapeutically exploited in non-APL malignancies.

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Acknowledgements

The laboratory of H.d.T. is supported by the Ligue Nationale contre le Cancer, the Cartes d'Identité des Tumeurs program, the Institut National de la Santé et de la Recherché Médicale (INSERM), the Centre National de la Recherché Scientifique (CNRS), University Paris Diderot, Institut Universitaire de France, Institut National du Cancer, Fondation Association pour la Recherche contre le Cancer (ARC) (Prix Griffuel) and the European Research Council (senior grant 268729 – STEMAPL). J.A. was supported by a fellowship from Ecole Polytechnique and Fondation ARC, K.R. by a fellowship from the Lady Tata and ARC Foundations. S.M. is supported by grants from EPIGEN and the Italian Association for Cancer Research (AIRC). We thank A. Janin, F. Bouhidel and P. Bertheau for assistance with mouse pathology; P. Chambon (Institut de Génétique et de Biologie Moléculaire et Cellulaire) for RARA-specific antibody; S. Lowe (Memorial Sloan-Kettering Cancer Center) for shRNA vectors and Pml-specific antibody; L. Peres and S. Gressens for technical help; M. Pla for the animal facility; N. Setterblad for imaging; E. Del Neyri and V. Dessirier for imaging statistical analysis; and I. Pallavicini and A. Marinelli for mouse work in Milan. We thank E. Raffoux, C. Bailly, P. Fenaux and N. Boissel (Hôpital St. Louis) for providing the patients' blood samples. We thank R. Ohki and L. Attardi for sharing unpublished p53 ChIP-Seq data. We thank all members of the laboratory of H.d.T. for helpful discussions, J. Godet for continuous support and V. Lallemand-Breitenbach, U. Sahin, S. Benhenda, F. Sigaux and J.C. Gluckman for critical reading of the manuscript.

Author information

Author notes

    • Julien Ablain

    Present address: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Affiliations

  1. Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris, France.

    • Julien Ablain
    • , Kim Rice
    • , Hassane Soilihi
    •  & Hugues de Thé
  2. INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France.

    • Julien Ablain
    • , Kim Rice
    • , Hassane Soilihi
    •  & Hugues de Thé
  3. CNRS UMR 7212, Hôpital St. Louis, Paris, France.

    • Julien Ablain
    • , Kim Rice
    • , Hassane Soilihi
    •  & Hugues de Thé
  4. Programme Cartes d'Identité des Tumeurs, Ligue Nationale contre le Cancer, Paris, France.

    • Aurélien de Reynies
  5. Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.

    • Saverio Minucci
  6. Department of Biosciences, University of Milan, Milan, Italy.

    • Saverio Minucci
  7. Assistance Publique Hôpitaux de Paris, Service de Biochimie, Hôpital St. Louis, Paris, France.

    • Hugues de Thé

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Contributions

J.A., H.S. and K.R. performed the experiments, J.A., A.d.R. and H.d.T. analyzed the bioinformatic data, S.M. provided reagents and discussed results and J.A., K.R. and H.d.T. analyzed the experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Hugues de Thé.

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DOI

https://doi.org/10.1038/nm.3441

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