PML–RARA degradation and PML nuclear body reformation underlie APL clearance by retinoic acid (RA).

  • Major finding: PML–RARA degradation and PML nuclear body reformation underlie APL clearance by retinoic acid (RA).

  • Mechanism: RA induces p53-dependent cell-cycle arrest and features of senescence that block APL self-renewal.

  • Impact: Treatment of malignancies other than APL may benefit from targeting nuclear body biogenesis.

The promyelocytic leukemia–retinoic acid receptor-α (PML–RARA) fusion protein drives initiation of acute promyelocytic leukemia (APL) by disrupting RARA-mediated signaling and the assembly of PML-containing nuclear bodies (NB). Most patients with APL can be cured by treatments combining retinoic acid (RA) and arsenic trioxide (arsenic). APL eradication by RA and arsenic is dependent on the ability of these agents to induce PML–RARA degradation, but the underlying mechanism of how PML–RARA loss leads to cure of APL remains unknown. Ablain and colleagues analyzed the effect of high RA doses in transgenic mice expressing the human PML–RARA fusion gene and found that enhanced survival and RA-mediated APL clearance was not explained by the known ability of RA to drive terminal granulocytic differentiation, but instead by the capacity of RA to cause cell-cycle arrest in PML–RARA-expressing cells. Gene expression analysis indicated activation of a senescent phenotype involving expression of several binding partners and transcriptional targets of p53, and p53 was essential for RA-mediated clearance of APL in vivo and ex vivo. In addition, RA treatment induced NB reformation downstream of PML–RARA degradation and p53 protein stabilization, raising the possibility that PML-mediated NB assembly following loss of PML–RARA was important for p53 activation and APL clearance by RA. In support of this idea, Pml−/− mice showed impaired RA-mediated PML–RARA APL clearance and dramatically reduced expression of a p53 gene signature including senescence-associated genes. Interestingly, arsenic further stimulated RA-initiated NB reformation in PML–RARA cells. These data may explain how the combination of RA and arsenic has synergistic effects in eliminating APL and suggest that NB biogenesis may be a potential therapeutic target in other types of cancers.

Ablain J, Rice K, Soilihi H, de Reynies A, Minucci S, de Thé H. Activation of a promyelocytic leukemia–tumor protein 53 axis underlies acute promyelocytic leukemia cure. Nat Med 2014 Jan 14 [Epub ahead of print].

©2014 American Association for Cancer Research.
2014