Caspase-1-mediated GATA1 cleavage and inflammasome activation drive myeloid bias in fanconi anemia: implications for targeted therapy 2986

Abstract Description Fanconi anemia (FA) is a rare genetic disorder marked by bone marrow failure (BMF) and heightened cancer risk. This study reveals the critical role of caspase-1 activation in promoting myeloid skewing through GATA1 cleavage and inflammasome activation in FA, suggesting a novel inflammatory mechanism underlying FA pathogenesis. In Fancc-deficient mice, we observed heightened inflammatory responses, including sensitivity to LPS-induced septic shock and increased caspase-1 activation in bone marrow-derived macrophages, leading to higher levels of cleaved IL-1β. Mechanistically, FANCC deficiency triggered caspase-1-mediated cleavage of GATA1, altering the GATA1/SPI1 balance in HSPCs and shifting differentiation towards myeloid lineages. Caspase-1 inhibition restored GATA1 levels, favoring erythroid differentiation in Fancc-deficient cells. In colony assays, Fancc-deficient HSPCs cultured with IL-1β showed a colony formation restricted to granulocyte-macrophage types, underscoring a myeloid bias. To explore potential therapeutic approaches, we used CRISPR to generate Fancc/Nlrp3 double knockout HSPCs, which rescued the defects in GATA1 cleavage and restored erythroid colony formation. This indicates that caspase-1 activation through the NLRP3 inflammasome is central to the inflammatory and differentiation abnormalities seen in FA. Our findings underscore the therapeutic potential of targeting the caspase-1/IL-1β pathway to correct myeloid skewing and prevent BMF in FA. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)