Somatic gene mutations expose cytoplasmic DNA to co-opt the cGAS/STING/NLRP3 axis in myelodysplastic syndromes

McLemore, Amy FAmy FMcLemoreHSIN-AN HOUMeyer, Benjamin SBenjamin SMeyerLam, Nghi BNghi BLamWard, Grace AGrace AWardAldrich, Amy LAmy LAldrichRodrigues, Matthew AMatthew ARodriguesVedder, AlexisAlexisVedderZhang, LingLingZhangPadron, EricEricPadronVincelette, Nicole DNicole DVinceletteSallman, David ADavid ASallmanAbdel-Wahab, OmarOmarAbdel-WahabList, Alan FAlan FListMcGraw, Kathy LKathy LMcGraw2023-03-082023-03-082022-08-082379-3708https://scholars.lib.ntu.edu.tw/handle/123456789/629032NLRP3 inflammasome and IFN-stimulated gene (ISG) induction are key biological drivers of ineffective hematopoiesis and inflammation in myelodysplastic syndromes (MDSs). Gene mutations involving mRNA splicing and epigenetic regulatory pathways induce inflammasome activation and myeloid lineage skewing in MDSs through undefined mechanisms. Using immortalized murine hematopoietic stem and progenitor cells harboring these somatic gene mutations and primary MDS BM specimens, we showed accumulation of unresolved R-loops and micronuclei with concurrent activation of the cytosolic sensor cyclic GMP-AMP synthase. Cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) signaling caused ISG induction, NLRP3 inflammasome activation, and maturation of the effector protease caspase-1. Deregulation of RNA polymerase III drove cytosolic R-loop generation, which upon inhibition, extinguished ISG and inflammasome response. Mechanistically, caspase-1 degraded the master erythroid transcription factor, GATA binding protein 1, provoking anemia and myeloid lineage bias that was reversed by cGAS inhibition in vitro and in Tet2-/- hematopoietic stem and progenitor cell-transplanted mice. Together, these data identified a mechanism by which functionally distinct mutations converged upon the cGAS/STING/NLRP3 axis in MDS, directing ISG induction, pyroptosis, and myeloid lineage skewing.enHematology; Leukemias; Oncology[SDGs]SDG3Somatic gene mutations expose cytoplasmic DNA to co-opt the cGAS/STING/NLRP3 axis in myelodysplastic syndromesjournal article10.1172/jci.insight.159430357881172-s2.0-85135599806WOS:000838790600001https://api.elsevier.com/content/abstract/scopus_id/85135599806