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Circulating Oxidized Mitochondrial DNA is an Index of Pyroptotic Cell Death in Patients with Myelodysplastic Syndrome.
EP27173
Poster Title: Circulating Oxidized Mitochondrial DNA is an Index of Pyroptotic Cell Death in Patients with Myelodysplastic Syndrome.
Submitted on 09 Feb 2018
Author(s): Grace A. Ward B.S., Kathy L. McGraw PhD., Ashley A. Basiorka PhD., Alan F. List M.D.
Affiliations: University of South Florida, Moffitt Cancer Center
This poster was presented at USF Research Day 2018
Poster Views: 407
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Poster Information
Abstract: Myelodysplastic Syndromes (MDS) are bone marrow failure diseases. We recently demonstrated that cell death in MDS arises from pyroptosis mediated through the Nod-like receptor 3 (NLRP3) inflammasome. Oxidized DNA (oxDNA) serves as a danger-associated molecular pattern (DAMP) that can amplify cell death by direct engagement and activation of NLRP3, as well as the DNA-recognition receptors Toll-like receptor (TLR)-9 and cGAS–STING. Upon inflammasome activation, caspase-1 is bridged to the nod like receptor NLRP3 through the adapter molecule, ASC, then undergoes autocleavage which subsequently cleaves pro-IL1β to drive a feed forward inflammatory cascade. Oxidized mitochondrial DNA (oxDNA) leaks to the cytosol upon mitochondrial membrane depolarization and is consequently released from pyroptotic progenitors upon cytolysis. We hypothesize that oxDNA is elevated in the peripheral blood (PB) of MDS patients and correlates with surrogate markers of pyroptosis. We analyzed oxDNA and other markers of pyroptosis by ELISA. Our data demonstrate that oxDNA is profoundly elevated in the peripheral blood of MDS patients compared to healthy donors, and increases directly with surrogate biomarkers of pyroptosis. Summary: We recently demonstrated that cell death in Myelodysplastic Syndromes (MDS) arises from pyroptosis mediated by the NLRP3 inflammasome. Oxidized mitochondrial DNA (oxDNA) leaks to the cytosol upon mitochondrial membrane depolarization and is released upon cytolysis. OxDNA serves as a DAMP that can amplify cell death through NLRP3, TLR-9 and cGAS–STING. Our data demonstrate that oxDNA is profoundly elevated in the MDS patients compared to healthy donors and increases with biomarkers of pyroptosis.References: Basiorka, 2016, Blood
Grishman, Pediatric Research, 2012
Shimada, 2012, Immunity.
Vollmer, 2004, Immunology
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