Objective
In acute promyelocytic leukaemia (APL), retinoic acid (RA) and Arsenic trioxide (As) bind PML/RARA and promote its degradation. Exploring the mechanistic bases for APL response to the RA/As combination, we found that upon PML/RARA degradation the normal PML allele activates a PML/P53 checkpoint absolutely required for APL cure in mice or patients. Physiologically, PML behaves as an oxidative stress sensor and contributes to redox homeostasis. PML organizes nuclear bodies (NBs), domains that recruit multiple client proteins and may facilitate their post-translational modifications (PTM), particularly conjugation of SUMOs. This somehow controls multiple downstream pathways such as P53, but also RB, HIF1A or interferon (IFN). In APL, NB-disruption blunts P53-driven senescence, contributing to oncogenesis and therapy resistance. Critically, PML expression and/or NB-formation are lost upon many viral infections or during cancer development. The mechanism(s) underlying the selective pressure to loose PML expression in multiple cancers remains incompletely understood.
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/P53-driven senescence in three leukaemia models where we have evidence for basal or therapy-responsive NB-modulation: acute myeloid leukaemia expressing NPMc and IFN-sensitive Tax- or JAK2-driven leukaemias. 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
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciences biological sciences biochemistry biomolecules proteins
- social sciences sociology governance taxation
- engineering and technology electrical engineering, electronic engineering, information engineering electronic engineering sensors
- medical and health sciences clinical medicine oncology leukemia
- medical and health sciences basic medicine physiology homeostasis
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-ADG - Advanced Grant
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2017-ADG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
75654 PARIS
France
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.