Apart from surgery, cancers are currently treated with very diverse approaches (chemotherapy, hormonal therapy, targeted therapies, radiotherapies, immunotherapies) How exactly these therapies yield clinical benefit in patients has been a matter of some controversies. Basic science is thus essential to understand the molecular and cellular bases for therapy response, notably to optimize drug combinations. In a specific form of AML, acute promyelocytic leukaemia (APL), we previously unravelled (with ERC support) the molecular basis for response to arsenic therapy, demonstrating that the PML protein plays a key role. Physiologically, PML behaves as an oxidative stress sensor and contributes to redox homeostasis. PML organizes nuclear bodies (NBs), domains that recruit multiple client proteins to facilitate their post-translational modifications (PTM), particularly conjugation of SUMOs. This controls multiple downstream pathways such as P53, but also cell cycle progression or interferon signalling (IFN). In APL, NB-disruption blunts P53-driven senescence, contributing to oncogenesis and therapy resistance. Therapy-induced NB-restoration is required for efficient APL clearance. More broadly, PML expression and/or NB-formation are lost upon many viral infections or during cancer development.
We are interested in the mechanistic basis of therapy response of acute myeloid leukaemia (AML). In the context of the current ERC grant, we want to explore the possibility that PML may play a role in AML responses to other therapies. Unravelling novel molecular mechanisms associated with therapy response will foster novel therapeutic approaches, notably drug combinations, that have immediate societal impact. Our aim is to mechanistically dissect PML signalling in vivo and therapeutically restore it in malignancies where it is inactivated. We first propose a broad exploration of PML in mice to identify basal and stress-induced PML PTM and identify the repertoire of proteins sumoylated in a PML- dependent manner. We will generate a series of PML knock-in mutant mice and analyse their P53-regulated redox homeostasis. We will mechanistically explore PML-driven senescence in leukaemia models where we have evidence for basal or therapy-responsive NB-modulation: acute myeloid leukaemia expressing NPMc or IFN-sensitive JAK2-driven leukaemia. We will screen chemical libraries for drugs modulating PML expression and/or NB biogenesis. Finally, we will integrate our findings to elaborate innovative therapeutic strategies based on restoration of the PML/P53 checkpoint in leukaemia with unmet medical needs.
Over the course of the complete grant, we have provided unambiguous evidence that PML indeed plays a key role in therapeutic response in multiple forms of acute leukaemia. In particular, in JAK2-driven myeloproliferative neoplasms, we demonstrated that the know therapeutic effects of IFN are boosted by arsenic, in a PML-dependent manner. Similarly, in NPM1c-driven AMLs, we found that Actinomycin D, an approved anti-cancer drug, has clinical activity through induction of ROS that target PML. Mechanistically, we identified the arsenic-binding site of PML, a solvent-exposed cysteine residue that appears to be the ROS-sensing site. Finally, we demonstrated that conventional AML chemotherapy requires PML presence for a full efficacy. Fine structure-function analyses have been performed and point to specific molecular mechanisms.
Overall, our work has positioned PML as a central hub of stress response, notably for the response to cancer therapies. PML is already targetable by arsenic, but newer PML-targeting agents may be discovered in the future. More broadly, our studies bring novel vision to the molecular and cellular mechanisms contributing to the clinical activity of conventional AML chemotherapies.
