Project description
Understanding PML nuclear bodies disruption in the context of AML treatment
A better understanding of the onset and development of acute myeloid leukaemia (AML) may lead to new therapeutic strategies. Acute promyelocytic leukaemia (APL), a subset of AML, can be successfully cured by combination therapy. Therefore, understanding the mechanisms underlying the pathogenesis and successful treatment of APL will improve the management of AML subsets with a poor prognosis. Promyelocytic leukaemia nuclear bodies (PML NBs), an archetype of membrane-less organelles that concentrate proteins at discrete sites within the nucleoplasm, are essential for APL pathogenesis and treatment response. The EU-funded PMLingAML project will elucidate the mechanisms of PML NBs disruption in APL, aiming to apply this knowledge in the treatment of other AML subsets.
Objective
Understanding the initiation and development of acute myeloid leukemia (AML) represents an important challenge which may lead to the identification of new therapeutic strategies. Acute promyelocytic leukemia (APL) was formerly the most lethal subset of AML; however, today the vast majority of APL patients can be cured by combination therapy. Therefore, fully understanding the mechanisms underlying successful treatment, by analysing the biology of APL pathogenesis will assuredly improve the management of AML subsets associated with a poor outcome, such as NPM1-mutated AML. Using a novel knock-in mouse model, PmlC62A/C65A, which mimics Pml nuclear body (NB) disruption induced by the main oncoprotein PML-RARα in APL, we have previously shown that Pml NBs are essential in APL pathogenesis and treatment response. Our project “PMLingAML” aims to carry on elucidating the impact of Pml NB disruption in APL, and then to apply this knowledge in other AML subsets. To this end, a mass spectrometry analysis will be conducted on both hematopoietic stem and progenitor (LSK) cells and promyelocytes isolated from healthy and leukemic murine bone marrows, to decipher the consequences of Pml NB disruption on the SUMOylome. Next, since PML NBs and NPM1 share common cellular functions and characteristics, we will analyse the inter-relationship between them; their localisation and dynamics will be assessed according to their respective status (disruption, mutation, knock-out), for example by high resolution imaging, both in various healthy and leukemic mouse models (incl NPM1c+ and NPM1c+/FLT3ITD), and in patient samples. Their respective roles in response to a drug under clinical trial, Dactinomycin, will also be scrutinised. Finally, as DNA damage repair is an important function disrupted during leukemogenesis, the roles of Pml NBs and Npm1 will be assessed together with their inter-relationship, with particular focus on the base excision repair (BER) pathway.
Fields of science
Keywords
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
75654 Paris
France