title: Unraveling the Pathogenesis of MDS: The NLRP3 Inflammasome and Pyroptosis Drive the MDS Phenotype.
abstract: Myelodysplastic syndromes (MDS) are characterized by bone marrow cytological dysplasia and ineffective hematopoiesis in the setting of recurrent somatic gene mutations and chromosomal abnormalities. The underlying pathogenic mechanisms that drive a common clinical phenotype from a diverse array of genetic abnormalities have only recently begun to emerge. Accumulating evidence has highlighted the integral role of the innate immune system in upregulating inflammatory cytokines via NF-κB activation in the pathogenesis of MDS. Recent investigations implicate activation of the NLRP3 inflammasome in hematopoietic stem/progenitor cells as a critical convergence signal in MDS with consequent clonal expansion and pyroptotic cell death though caspase-1 maturation. Specifically, the alarmin S100A9 and/or founder gene mutations trigger pyroptosis through the generation of reactive oxygen species leading to assembly and activation of the redox-sensitive NLRP3 inflammasome and β-catenin, assuring propagation of the MDS clone. More importantly, targeted inhibition of varied steps in this pathway restore effective hematopoiesis. Together, delineation of the role of pyroptosis in the clinical phenotype of MDS patients has identified novel therapeutic strategies that offer significant promise in the treatment of MDS.
authors.affiliation: Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL , USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Sallman
authors.affiliation: Hematology Department, Centre Hospitalier Universitaire of Nice, Nice, France; Faculty of Medicine, University Nice Sophia Antipolis, Nice, France; Mediterranean Center of Molecular Medicine, INSERM U1065, Nice, France; French Group of Myelodysplasia, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cluzeau
authors.affiliation: Cancer Biology Ph.D. Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida , Tampa, FL , USA.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Basiorka
authors.affiliation: Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL , USA.
authors.forename: Alan
authors.initials: A
authors.lastname: List
keywords: MDS; NLRP3; S100A9; TLR; inflammasome; pyroptosis