Description du projet
Comprendre la perturbation des corps nucléaires PML dans le cadre du traitement de la LAM
Une meilleure compréhension de l’apparition et du développement de la leucémie aiguë myéloblastique (LAM) pourrait déboucher sur de nouvelles stratégies thérapeutiques. La leucémie aiguë promyélocytaire (LAP), un sous-type de la LAM, peut être guérie avec succès par le biais d’une thérapie combinée. Par conséquent, la compréhension des mécanismes qui sous-tendent la pathogenèse et la réussite du traitement de la LAP permettront d’améliorer la gestion des sous-types de LAM au pronostic défavorable. Les corps nucléaires de la leucémie promyélocytaire (LPM), un archétype d’organites sans membrane qui concentrent les protéines sur des sites discrets dans le nucléoplasme, sont essentiels pour la pathogénèse de la LAP et la réponse au traitement. Le projet PMLingAML, financé par l’UE, permettra d’élucider les mécanismes de perturbation des corps nucléaires de la LPM dans la LAP, en vue d’appliquer ces connaissances au traitement d’autres sous-types de LAM.
Objectif
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.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
75654 Paris
France