Descrizione del progetto
Comprendere l’alterazione dei corpi nucleari della leucemia promielocitica nel contesto del trattamento della leucemia mieloide acuta
Una migliore comprensione dell’insorgenza e dello sviluppo della leucemia mieloide acuta (LMA) potrebbe condurre a nuove strategie terapeutiche. La leucemia promielocitica acuta, un sottoinsieme della leucemia mieloide acuta, può essere curata con successo attraverso la terapia di combinazione. Pertanto, la comprensione dei meccanismi alla base della patogenesi e il trattamento di successo della leucemia promielocitica acuta miglioreranno la gestione dei sottoinsiemi di leucemia mieloide acuta con una prognosi sfavorevole. I corpi nucleari della leucemia promielocitica (PML, Promyelocytic Leukaemia), un archetipo di organuli privi di membrana che concentrano proteine su siti discreti all’interno del nucleoplasma, sono essenziali per la patogenesi della leucemia promielocitica acuta e la risposta al trattamento. Il progetto PMLingAML, finanziato dall’UE, chiarirà i meccanismi dell’alterazione dei corpi nucleari della leucemia promielocitica nella leucemia promielocitica acuta, con l’obiettivo di applicare questa conoscenza nel trattamento di altri sottoinsiemi di leucemia mieloide acuta.
Obiettivo
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.
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
75654 Paris
Francia