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Nat Med. 2014 Feb;20(2):167-74. doi: 10.1038/nm.3441. Epub 2014 Jan 12.

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

Author information

1
1] Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris, France. [2] INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France. [3] CNRS UMR 7212, Hôpital St. Louis, Paris, France. [4].
2
1] Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris, France. [2] INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France. [3] CNRS UMR 7212, Hôpital St. Louis, Paris, France.
3
Programme Cartes d'Identité des Tumeurs, Ligue Nationale contre le Cancer, Paris, France.
4
1] Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. [2] Department of Biosciences, University of Milan, Milan, Italy.
5
1] Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris, France. [2] INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France. [3] CNRS UMR 7212, Hôpital St. Louis, Paris, France. [4] Assistance Publique Hôpitaux de Paris, Service de Biochimie, Hôpital St. Louis, Paris, France.

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.

PMID:
24412926
DOI:
10.1038/nm.3441
[Indexed for MEDLINE]

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