Project description
Exploiting retinoic acid receptor alpha signalling to treat acute myeloid leukaemia
The bone marrow of patients with acute myeloid leukaemia (AML) produces a large number of abnormal blood cells. Treatment depends on the AML subtype and often includes chemotherapy, which some patients cannot handle. Clinical trials have indicated that the addition of retinoic acid (RA) to conventional therapies can prove beneficial in some cases. Therefore, modulation of retinoic acid receptor alpha (RARA) signalling could be a target for effective treatment of non-promyelocytic AML. The ERC-funded RARA AML project has observed that overexpression of RARA serves to yield cell self-renewal ex vivo and RA-sensitivity in AML models. It now aims to determine the effects and cellular mechanisms behind this self-renewal to formulate novel treatment combinations.
Objective
In acute promyelocytic leukaemia (APL), retinoic acid (RA) and arsenic trioxide (ATO) bind the PML/RARA fusion to promote its degradation, derepressing unknown master regulatory genes and activating a PML/P53 checkpoint which is required for APL cure. APL initiation deregulates Retinoic Acid Receptor a (RARA) signalling. These deregulations are likely shared with a sizable subset of non-APL acute myeloid leukaemia (AML): the 30% that overexpress normal RARA and exhibit some RA-sensitivity ex vivo. Clinical trials have demonstrated some benefit of RA addition to conventional therapies in non-APL AML patients, but have not resulted in the incorporation of RA into standard therapies. Thus, modulation of RARA signalling is an unrealized target for treatment of non-APL AMLs.
Of importance, RARA serves a dual function in APL by promoting leukemogenesis in the unliganded state, but also by enforcing RA-response. We made the striking observation that overexpression of RARA suffices to confer cell self-renewal ex vivo and RA-sensitivity in several AML models. We propose to i) define the actual effects (differentiation, self-renewal) and cellular mechanisms (senescence, apoptosis, growth arrest) underlying RA action on a variety of primary myeloid cells over-expressing RARA ii) delineate the mechanism(s) underlying RARA overexpression in some human AMLs iii) identify the RARA downstream targets that drive self-renewal iv) discover novel RA-containing drug combinations exhibiting synergies for AML clearance in RA-sensitive transformed myeloid cells. This proposal is based on our previous modelling of APL therapy and recent disruptive observations. This renewed exploration of RARA-driven progenitor self-renewal will allow us to define novel curative RA-containing strategies and biomarkers for many AML patients unfit for chemotherapy, who are currently not eligible for cure.
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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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.
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Call for proposal
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(opens in new window) ERC-2023-ADG
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75654 PARIS
France
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