Description du projet
L’apoptose dans l’insuffisance de la moelle osseuse
L’apoptose est un processus hautement régulé de mort cellulaire programmée qui se produit naturellement dans l’organisme pour éliminer les cellules endommagées, vieilles ou inutiles. Elle joue un rôle crucial dans l’homéostasie tissulaire ainsi que dans la physiopathologie des syndromes héréditaires d’insuffisance de la moelle osseuse tels que l’anémie de Fanconi et la dyskératose congénitale, qui entraînent une diminution de la production de globules rouges et de globules blancs. Le projet ApoptoMDS, financé par l’UE, examinera les mécanismes de mort cellulaire dans les syndromes d’insuffisance médullaire héréditaire afin de décrypter l’impact de l’apoptose dans l’insuffisance médullaire et son rôle dans le développement de la leucémie. Les résultats poseront les bases de nouvelles approches thérapeutiques visant à soulager les symptômes des patients atteints de ces syndromes.
Objectif
Deregulated apoptotic signaling in hematopoietic stem and progenitor cells (HSPCs) strongly contributes to the pathogenesis and phenotypes of congenital bone marrow failure and myelodysplastic syndromes (MDS) and their progression to acute myeloid leukemia (AML). HSPCs are highly susceptible to apoptosis during bone marrow failure and early MDS, but AML evolution selects for apoptosis resistance. Little is known about the main apoptotic players and their regulators. ApoptoMDS will investigate the impact of apoptotic deregulation for pathogenesis, correlate apoptotic susceptibility with the kinetics of disease progression and characterize the mechanism by which apoptotic susceptibility turns into resistance. ApoptoMDS will draw on a large collection of patient-derived samples and genetically engineered mouse models to investigate disease progression in serially transplanted and xenotransplanted mice. How activated DNA damage checkpoint signaling contributes to syndrome phenotypes and HSPC hypersusceptibility to apoptosis will be assessed. Checkpoint activation confers a competitive disadvantage, and HSPCs undergoing malignant transformation are under high selective pressure to inactivate it. Checkpoint abrogation mitigates the hematological phenotype, but increases the risk of AML evolution. ApoptoMDS aims to analyze if inhibiting apoptosis in HSPCs from bone marrow failure and early-stage MDS can overcome the dilemma of checkpoint abrogation. Whether inhibiting apoptosis is sufficient to improve HSPC function will be tested on several levels and validated in patient-derived samples. How inhibiting apoptosis in the presence of functional checkpoint signaling influences malignant transformation kinetics will be assessed. If, as hypothesized, inhibiting apoptosis both mitigates hematological symptoms and delays AML evolution, ApoptoMDS will pave the way for novel therapeutic approaches to expand the less severe symptomatic period for patients with these syndromes.
Champ scientifique
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
79106 Freiburg
Allemagne