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Molecular Targets of Treatment in APL

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Acute Promyelocytic Leukemia

Abstract

Retinoic acid (RA) treatment of APL was long considered to be the hallmark model for differentiation therapy. Differentiation was attributed to reactivation of RA signaling upon activation of PML/RARA by its ligand. Over the years, evidence from mouse models has questioned the key role of transcriptional reactivation in clinical remissions. The striking activity of arsenic trioxide, a compound which does not affect normal RA, argued for the existence of other mechanisms. The ability of RA and arsenic to degrade PML/RARA progressively emerged as a central component of response. PML/RARA loss restores P53 signaling, by allowing the reformation of PML nuclear bodies (NBs). P53 activation drives loss of self-renewal and clearance of APL cells. Restoration of PML NBs is also facilitated by arsenic, which targets normal PML to enhance NB formation. Such dual targeting by arsenic of PML/RARA and PML likely explain its clinical superiority. Mutations that are associated with therapy resistance do not only occur on RA or arsenic binding sites, but also on the arsenic binding site of PML. Such direct involvement of PML and NBs in APL cure raises hopes for their harnessing in other leukemias or tumors.

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Authors and Affiliations

  1. Service Hématologie Séniors, Hôpital Saint-Louis, Assistance Publique—Hôpitaux de Paris, Paris, France

    Ramy Rahmé M.D.

  2. Université Paris Diderot, Paris, France

    Ramy Rahmé M.D.

  3. Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d’Hématologie, Hôpital St. Louis, Paris, France

    Ramy Rahmé M.D., Cécile Esnault Ph.D. & Hugues de Thé M.D., Ph.D.

  4. INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Hôpital St. Louis, Paris, France

    Ramy Rahmé M.D., Cécile Esnault Ph.D. & Hugues de Thé M.D., Ph.D.

  5. CNRS UMR 7212, Hôpital St. Louis, Paris, France

    Ramy Rahmé M.D., Cécile Esnault Ph.D. & Hugues de Thé M.D., Ph.D.

  6. Assistance Publique des Hôpitaux de Paris, Oncologie Moléculaire, Hôpital St. Louis, Paris, France

    Ramy Rahmé M.D. & Hugues de Thé M.D., Ph.D.

  7. Collège de France, PSL University, Paris, France

    Hugues de Thé M.D., Ph.D.

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  1. Division of Hematology/Oncology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada

    Oussama Abla

  2. Department of Hematology, University of Tor Vergata, Rome, Italy

    Francesco Lo Coco

  3. Department of Medicine, Hospital Universitari i Politecnic La Fe, University of Valencia, Valencia, Spain

    Miguel A. Sanz

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Rahmé, R., Esnault, C., de Thé, H. (2018). Molecular Targets of Treatment in APL. In: Abla, O., Lo Coco, F., Sanz, M. (eds) Acute Promyelocytic Leukemia . Springer, Cham. https://doi.org/10.1007/978-3-319-64257-4_2

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