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APL a model for oncogene-targeted leukemia cure

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.

Call for proposal

ERC-2010-AdG_20100317
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Host institution

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Address
Rue De Tolbiac 101
75654 Paris
France

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Activity type
Research Organisations
Administrative Contact
Dina Falkenreck (Ms.)
Principal investigator
Hugues, Marie, François Blaudin De Thé (Prof.)
EU contribution
€ 2 289 932,85

Beneficiaries (2)

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France
EU contribution
€ 2 289 932,85
Address
Rue De Tolbiac 101
75654 Paris

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Activity type
Research Organisations
Administrative Contact
Dina Falkenreck (Ms.)
Principal investigator
Hugues, Marie, François Blaudin De Thé (Prof.)
American University of Beirut
Lebanon
EU contribution
€ 210 067,15
Address
Bliss Street
1107 2020 Beirut

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Activity type
Higher or Secondary Education Establishments
Administrative Contact
Fadia Homeidan (Dr.)