Cellular senescence leads to acute promyelocytic leukemia cure

Targeted treatments for acute promyelocytic leukemia (PML), a rare form of blood cancer, cause a cascade of molecular events that lead to cellular senescence and recovery. This action model could be activated in other types of cancers.

The PML/retinoic acid receptor alpha (RARA) protein causes the proliferation of cancer cells in patients affected by acute PML. The majority of patients make a permanent recovery thanks to existing targeted treatments that combine the hormone retinoic acid and the poison arsenic. Prior to this research, their exact action on cancer cells was unknown.

This work, conducted by Hugues de Thé, MD, PhD, and his team at Paris Diderot University in France, built on their previous work that showed that combining arsenic and retinoic acid caused the destruction of the PML/RARA protein and the elimination of leukemic stem cells. The current work clarifies the link between these two events.

During this targeted treatment, researchers showed that the p53 protein, which is an arbiter between cell death and survival, triggers senescence through the involvement of PML nuclear bodies. Cells in senescence are in a final aging stage and are incapable of multiplying.

PML nuclear bodies are spherical structures that are present in normal cells but get disorganized by the PML/RARA protein in leukemia. The treatment reorganizes them by activating p53 and triggering senescence. In this cascade of events (treatment, PML/RARA degradation, reformation of nuclear bodies, and p53 activation), only one link has to be missing to block all the therapeutic effects.

This phenomenon enables the elimination of diseased cells and leads to total recovery of the patient, using only combined retinoic acid/arsenic treatment. The absence of chemotherapy avoids many severe side effects.

This understanding of the cellular and molecular mechanism of recovery from acute PML opens prospects for activating this same PML/p53 pathway in other types of cancers. The biogenesis of nuclear bodies is druggable, so it has the potential to be exploited in nonacute PML.

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