Equipe d’Accueil : Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications
Intitulé de l’Unité : INSERM U 1163
Nom du Responsable de l’Unité : Pr Bana JABRI
Nom du Responsable de l’Équipe : Pr Olivier Hermine
Adresse : Institut IMAGINE- 24 boulevard du Montparnasse 75015 Paris, France
Responsable de l’encadrement : Dr Leïla MAOUCHE CHRETIEN
Tél : (+33) 01 42 75 42 79  E-mail : leila.maouche@inserm.fr

Résumé du projet 

Topic of the project: We are interested in mastocytosis, a rare and heterogeneous disease characterized by an accumulation of abnormal mast cells in the tissues. The disease can be exclusively cutaneous, systemic indolent or systemic aggressive, such as mast cell leukemia. In 85% of patients, a somatic KIT D816V mutation is detected in the tumoral cells ; however, a deregulated KIT pathway is not sufficient to induce the disease and cannot explain the heterogeneity of the pathology. Other events are required for disease onset, and we have previously published that KIT mutation cooperates with germline mutations to develop mastocytosis (PMID: 34424959).

Using genetic approaches, we identified patients carrying both a somatic KIT D816V mutation and a germline mutation in a gene involved in apoptosis. We have also identified patients with varying disease severity who express different levels of this gene, even in the absence of mutations. These preliminary data suggest that the dysregulation of our candidate gene may be a key determinant of mastocytosis.
Aim of the Master project: The objective of this internship is to employ base editing technology to introduce the mutation, identified in the patients, into two distinct mast cell lines: one expressing wild-type KIT and the other expressing KIT D816V. This strategy will allow us to study the potential oncogenic cooperation between the apoptosis gene mutation and KIT D816V. Subsequently, we will assess the proliferation and apoptosis responses of these modified cell lines. This project aims to validate our hypothesis regarding the role of the candidate gene in the pathophysiology of mastocytosis.
During the internship, the Master student will learn several techniques of cell biology, biochemistry and molecular biology such as: cell culture, base editing, proliferation kinetics, apoptosis assays, FACS and Western blot.

Ce projet s’inscrit dans la perspective d’une thèse
Type de financement prévu : Bourse du ministère
Ecole Doctorale de rattachement : HOB

Dernières Publications en lien avec le projet :
Guillaume Lefèvre et al, : Interactions Between Eosinophils and IL5Rα+ Mast Cells in Non-Advanced Systemic Mastocytosis. J Allergy Clin Immunol. 2024 Dec. PMID: 39151478

Maël Heiblig et al, Comparison of prognostic scores according to WHO classification in 170 patients with advanced mastocytosis and C-finding treated with midostaurin. Am J Hematol. 2024 Nov. PMID: 39287048

L. Polivka, et al : The association of Greig syndrome and mastocytosis reveals the involvement of the hedgehog pathway in advanced mastocytosis. Blood. 2021 Dec. PMID: 34424959

Laura Polivka et al, : Criteria for the Regression of Pediatric Mastocytosis: A Long-Term Follow-Up. J Allergy Clin Immunol Pract. 2021 Apr. PMID: 33338682

Rossignol J et al, : Recent advances in the understanding and therapeutic management of mastocytosis. F1000Res. 2019 Nov . PMID: 31824655