Credit: The Armed Forces
Institute of Pathology
Results of a new study appear to explain how retinoic acid and arsenic trioxide work against acute promyelocytic leukemia (APL).
Researchers found that retinoic acid, either alone or in combination with arsenic trioxide, causes a cascade of molecular events that lead to cellular senescence.
And this halts APL-initiating activity in patient samples and mouse models of the disease.
The team said this mechanism could be activated to fight malignancies other than APL as well.
Hugues de Thé, MD, PhD, of Université Paris Diderot in France, and his colleagues described this research in Nature Medicine.
The group knew that APL is driven by the promyelocytic leukemia-retinoic acid receptor fusion protein (PML-RARA), which interferes with nuclear receptor signaling and PML nuclear body assembly.
Furthermore, APL can be cured by retinoic acid and arsenic trioxide (alone or in combination), both of which trigger PML-RARA degradation through non-overlapping pathways.
However, exactly how these treatments work in APL has been unclear. Dr de Thé’s research indicates that both drugs incite a cascade of events leading to senescence.
The researchers found evidence suggesting that a functional PML-transformation-related protein 53 (Trp53) axis is required to halt APL-initiating activity.
When retinoic acid induces PML-RARA degradation, normal PML elicits nuclear body reformation and prompts a Trp53 response that exhibits features of senescence. And this halts APL-initiating activity.
In addition, normal PML seems to play a role in the synergy between retinoic acid and arsenic trioxide. The researchers discovered that arsenic increases retinoic acid-induced PML-RARA degradation.
But arsenic also appears to cooperate with retinoic acid to cure APL by binding PML, accelerating nuclear body reformation, and enhancing downstream TP53 signaling.
The researchers said it seems likely that the same PML/p53 pathway can be activated in cancers other than PML as well.
