Objective Acute promyelocytic leukaemia, APL, is probably one of the best-understood malignancies and the only one where highly efficient oncogene-targeted therapies (retinoic acid and arsenic) actually cure the disease. Our recent studies have addressed the molecular basis for transformation and demonstrated the essential role of sumoylation of the PML moiety of PML/RARA, relaxed DNA-binding specificity, binding to RXRA, for both transcriptional repression and transformation in primary cells, uncovering an unexpected level of complexity for in vivo transformation. We have also explored PML nuclear bodies (NB) formation, enigmatic structures that are disrupted by PML/RARA expression, restored by either RA or arsenic and may thus contribute to transformation/response. Exploring the actual basis for therapy response, we have provide some evidence that PML/RARA degradation and loss of leukaemia-initiating cells, rather than differentiation, is key to APL clearance.We propose to address the following issues: i) genetically uncouple differentiation from APL eradication ii) model transformation and therapy response iii) analyse the regulation and role of PML NBs iv) explore other models where degradation of the driving oncogene may eradicate the disease through loss of LIC activity.These studies should not only provide a complete model for APL pathogenesis and treatment response, but also open new avenues in the field of PML nuclear body biogenesis and function, as well as transcriptional activation/degradation coupling. The proposed research could provide generally applicable strategies for a variety of malignancies that are similarly driven by fusion proteins. As previously, in the APL and Adult T cell leukaemia models, our studies could also yield new directly clinically applicable therapeutic strategies. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural scienceschemical sciencesinorganic chemistrymetalloidsmedical and health sciencesclinical medicineoncologyleukemia Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS4 - ERC Advanced Grant - Physiology, Pathophysiology and Endocrinology Call for proposal ERC-2010-AdG_20100317 See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Host institution INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE EU contribution € 2 289 932,85 Address RUE DE TOLBIAC 101 75654 Paris France See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Administrative Contact Dina Falkenreck (Ms.) Principal investigator Hugues, Marie, François Blaudin De Thé (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (2) Sort alphabetically Sort by EU Contribution Expand all Collapse all INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE France EU contribution € 2 289 932,85 Address RUE DE TOLBIAC 101 75654 Paris See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Administrative Contact Dina Falkenreck (Ms.) Principal investigator Hugues, Marie, François Blaudin De Thé (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data American University of Beirut Lebanon EU contribution € 210 067,15 Address BLISS STREET 1107 2020 Beirut See on map Activity type Higher or Secondary Education Establishments Administrative Contact Fadia Homeidan (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
