Journal
NATURE MEDICINE
Volume 20, Issue 2, Pages 167-174Publisher
NATURE PORTFOLIO
DOI: 10.1038/nm.3441
Keywords
-
Funding
- Ligue Nationale contre le Cancer
- Cartes d'Identite des Tumeurs program
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Centre National de la Recherche Scientifique (CNRS)
- University Paris Diderot
- Institut Universitaire de France
- Institut National du Cancer
- Fondation Association pour la Recherche contre le Cancer (ARC) (Prix Griffuel)
- European Research Council [268729 - STEMAPL]
- Ecole Polytechnique
- Fondation ARC
- Lady Tata Foundation
- ARC Foundation
- EPIGEN
- Italian Association for Cancer Research (AIRC)
Ask authors/readers for more resources
Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-a (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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available