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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arsenic Trioxide
  • Arsenicals / pharmacology
  • Computational Biology
  • Humans
  • Kaplan-Meier Estimate
  • Leukemia, Promyelocytic, Acute / drug therapy*
  • Leukemia, Promyelocytic, Acute / metabolism
  • Mice
  • Microarray Analysis
  • Nuclear Proteins / metabolism*
  • Oxides / pharmacology
  • Promyelocytic Leukemia Protein
  • Proteolysis / drug effects
  • Receptors, Retinoic Acid / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / 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*

Substances

  • 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

Associated data

  • GEO/GSE51723