Project description DEENESFRITPL Apoptosis in bone marrow failure Apoptosis is a highly regulated process of programmed cell death that occurs naturally in the body to remove damaged, old, or unnecessary cells. It plays a crucial role in tissue homeostasis as well as in the pathophysiology of inherited bone marrow failure syndromes such as Fanconi anaemia and dyskeratosis congenita, leading to a decreased production of red blood cells and white blood cells. The EU-funded ApoptoMDS project will examine the mechanisms of cell death in inherited bone marrow failure syndromes to decipher the impact of apoptosis in bone marrow failure and its role in the development of leukaemia. Results will lay the foundation for novel therapeutic approaches to alleviate symptoms of patients with these syndromes. Show the project objective Hide the project objective Objective 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. Fields of science natural sciencesbiological sciencesgeneticsDNAmedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicinehematologymedical and health sciencesclinical medicineoncologyleukemia Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-StG-2014 - ERC Starting Grant Call for proposal ERC-2014-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Coordinator UNIVERSITAETSKLINIKUM FREIBURG Net EU contribution € 1 372 525,00 Address Hugstetter strasse 49 79106 Freiburg Germany See on map Region Baden-Württemberg Freiburg Freiburg im Breisgau, Stadtkreis Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSITAETSKLINIKUM FREIBURG Germany Net EU contribution € 1 372 525,00 Address Hugstetter strasse 49 79106 Freiburg See on map Region Baden-Württemberg Freiburg Freiburg im Breisgau, Stadtkreis Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
