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ERC

STEMAPL Report Summary

Project ID: 268729
Funded under: FP7-IDEAS-ERC
Country: France

Final Report Summary - STEMAPL (APL a model for oncogene-targeted leukemia cure)

The goal of STEMAPL was to understand how two drugs (retinoic acid (RA) and arsenic) act in a specific subtype of myeloid leukemia. We had demonstrated that these two drugs directly bind PML/RARA, the driving oncoprotein in this condition and promote its degradation.
The ERC support has allowed us to demonstrate that therapy-induced degradation of PML/RARA allows the re-assembly of distinct nuclear domains known as PML nuclear bodies.

These act as post-translational modification factories which participate in stress response. We demonstrated using mice models that in this condition, therapy-induced PML nuclear body reformation activates a senescence program that comprises activation of the P53 tumor suppressor. Interestingly, PML bodies are known markers of senescent cells. This RA- or arsenic-initiated PML/P53 checkpoint is absolutely required for the definitive clearance of the disease. Remarkably, we demonstrated the existence of mutations in PML (and not only in PML/RARA, as expected) in therapy-resistant patients, thus fully validating in patients the physio-pathological model. During the contract, our previous work, supporting the potency of the frontline association of the two drugs was dramatically illustrated by prospective clinical trials. The frontline RA/Arsenic combination, whose action is now largely understood thanks to ERC, has now become the gold standard all over the world, curing over 95% of treated patients without DNA-damaging therapy.

This example represents a success of targeted therapy, demonstrates that oncoprotein degradation is a feasible therapeutic goal and highlights one of the rare conditions where the biochemical and cellular activities of an anticancer therapy is understood in significant details. In principle, this PML/P53 senescence checkpoint could be activated and may drive benefit in some other forms of leukemia. In that respect, significant pieces of evidence were provided to understand the assembly and biochemical roles of PML nuclear bodies.

* Please, notice that this summary may be published

Reported by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM)
France
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