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

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.

• Authors: Julien Ablain, Kim Rice, Hassane Soilihi, Aurélien de Reynies, Saverio Minucci, Hugues de Thé
• Journal: Nature medicine (Nat Med) Vol. 20 Issue 2 Pg. 167-74 (Feb 2014) ISSN: 1546-170X [Electronic] United States
• PMID: 24412926 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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)