title: The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype.
abstract: Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and β-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention.
authors.affiliation: Cancer Biology Ph.D. Program, Department of Malignant Hematology.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Basiorka
authors.affiliation: Department of Malignant Hematology.
authors.forename: Kathy L
authors.initials: KL
authors.lastname: McGraw
authors.affiliation: Department of Immunology.
authors.forename: Erika A
authors.initials: EA
authors.lastname: Eksioglu
authors.affiliation: Department of Immunology.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Analytic Microscopy Core Facility, and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Hematopathology, H. Lee Moffitt Cancer Center, Tampa, FL.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Malignant Hematology.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Malignant Hematology.
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Irvine
authors.affiliation: Department of Hematology, Centre Hospitalier Universitaire de Nice, Nice, France.|Faculty of Medicine, University Nice Sophia Antipolis, Nice, France.|INSERM U1065, Mediterranean Center of Molecular Medicine, Nice, France.|French Group of Myelodysplasia, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cluzeau
authors.affiliation: Department of Malignant Hematology.
authors.forename: David A
authors.initials: DA
authors.lastname: Sallman
authors.affiliation: Department of Malignant Hematology.
authors.forename: Eric
authors.initials: E
authors.lastname: Padron
authors.affiliation: Department of Malignant Hematology.
authors.forename: Rami
authors.initials: R
authors.lastname: Komrokji
authors.affiliation: Department of Malignant Hematology.
authors.forename: Lubomir
authors.initials: L
authors.lastname: Sokol
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Coll
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
authors.forename: Avril A B
authors.initials: AA
authors.lastname: Robertson
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL; and.
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
authors.affiliation: Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
authors.forename: Luke A
authors.initials: LA
authors.lastname: O'Neill
authors.affiliation: Department of Immunology.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Malignant Hematology.
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
mesh_terms: D000818:Animals; D040502:Calgranulin B / Q000378:metabolism; D048429:Cell Size; D003114:Colony-Forming Units Assay; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology*; D019255:NADPH Oxidases / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010641:Phenotype; D000069292:Pyroptosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D040502:Calgranulin B; D058847:Inflammasomes; D007473:Ion Channels; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; D051176:beta Catenin; D019255:NADPH Oxidases