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.
MeSH 主题词
Animals
Arsenic Trioxide
Arsenicals/pharmacology
Computational Biology
Humans
Kaplan-Meier Estimate
Leukemia, Promyelocytic, Acute/drug therapy,metabolism
Mice
Microarray Analysis
Nuclear Proteins/metabolism
Oxides/pharmacology
Promyelocytic Leukemia Protein
Proteolysis/drug effects
Receptors, Retinoic Acid/metabolism
Recombinant Fusion Proteins/metabolism,pharmacology
Retinoic Acid Receptor alpha
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction/physiology
Transcription Factors/metabolism
Tretinoin/pharmacology
Tumor Suppressor Protein p53/metabolism
Tumor Suppressor Proteins/metabolism
化学物质
Arsenicals
Nuclear Proteins
Oxides
Pml protein, mouse
Promyelocytic Leukemia Protein
RARA protein, human
Rara protein, mouse
Receptors, Retinoic Acid
Recombinant Fusion Proteins
Retinoic Acid Receptor alpha
Transcription Factors
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Tretinoin
Arsenic Trioxide
作者与单位
共 6 位作者，点击展开单位 / ORCID
Ablain Julien
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].
Rice Kim
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.
Soilihi Hassane
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.
de Reynies Aurélien
Programme Cartes d'Identité des Tumeurs, Ligue Nationale contre le Cancer, Paris, France.
Minucci Saverio
1] Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. [2] Department of Biosciences, University of Milan, Milan, Italy.
de Thé Hugues
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.
