Acute promyelocytic leukaemia: novel insights into the mechanisms of cure

Key Points Promyelocytic leukaemia (PML)–retinoic acid receptor-α (RARα) is a gain-of-function protein that represses RARα and non-RARα target genes and disrupts PML nuclear bodies. This results in immortal proliferation and the inhibition of terminal differentiation. Various clinical regimens combining retinoic acid (RA), arsenic trioxide and anthracyclines now definitively cure up to 90% of patients with acute promyelocytic leukaemia (APL). RA induces APL differentiation and transient remissions. Arsenic trioxide triggers both apoptosis and differentiation and, as a single agent, allows many APL cures. As initially shown in mouse models, their combination definitively cures most patients. Mechanistically, therapy-induced transcriptional activation (or derepression) is responsible for APL cell differentiation, and PML–RARα degradation by RA or arsenic trioxide results in APL eradication. Arsenic trioxide targets PML through oxidation-triggered disulphide bond formation and direct binding. This results in PML and PML–RARα sumoylation, ubiquitylation and proteasome-mediated degradation. Therapy-triggered oncoprotein degradation could be a generally applicable strategy to treat malignancies driven by fusion proteins or overactivation of transcription factors. This Review discusses the new data that have revealed surprising insights into the pathogenesis of acute promyelocytic leukaemia (APL) and the mechanism by which retinoic acid plus arsenic trioxide combination therapy targets the oncogenic fusion protein promyelocytic leukaemia (PML)–retinoic acid receptor-α (RARα), curing most cases of APL. The fusion oncogene, promyelocytic leukaemia ( PML )–retinoic acid receptor-α ( RARA ), initiates acute promyelocytic leukaemia (APL) through both a block to differentiation and increased self-renewal of leukaemic progenitor cells. The current standard of care is retinoic acid (RA) and chemotherapy, but arsenic trioxide also cures many patients with APL, and an RA plus arsenic trioxide combination cures most patients. This Review discusses the recent evidence that reveals surprising new insights into how RA and arsenic trioxide cure this leukaemia, by targeting PML–RARα for degradation. Drug-triggered oncoprotein degradation may be a strategy that is applicable to many cancers.