The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka, Ashley A., McGraw, Kathy L., Eksioglu, Erika A., Chen, Xianghong, Johnson, Joseph, Zhang, Ling, Zhang, Qing, Irvine, Brittany A., Cluzeau, Thomas, Sallman, David A., Padron, Eric, Komrokji, Rami, Sokol, Lubomir, Coll, Rebecca C., Robertson, Avril A. B., Cooper, Matthew A., Cleveland, John L., O'Neill, Luke A., Wei, Sheng and List, Alan F. (2016) The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood, 128 25: 2960-2975. doi:10.1182/blood-2016-07-730556

Author Basiorka, Ashley A.
McGraw, Kathy L.
Eksioglu, Erika A.
Chen, Xianghong
Johnson, Joseph
Zhang, Ling
Zhang, Qing
Irvine, Brittany A.
Cluzeau, Thomas
Sallman, David A.
Padron, Eric
Komrokji, Rami
Sokol, Lubomir
Coll, Rebecca C.
Robertson, Avril A. B.
Cooper, Matthew A.
Cleveland, John L.
O'Neill, Luke A.
Wei, Sheng
List, Alan F.
Title The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
Publication date 2016-12-22
Year available 2016
Sub-type Article (original research)
DOI 10.1182/blood-2016-07-730556
Open Access Status Not yet assessed
Volume 128
Issue 25
Start page 2960
End page 2975
Total pages 16
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
Subject 1303 Biochemistry
2403 Immunology
2720 Hematology
1307 Cell Biology
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.
Keyword Nadph Oxidase Activation
Acute Myeloid-Leukemia
Error-Prone Repair
Genomic Instability
Increased Apoptosis
Oxidative Stress
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID K01 CA187020
P30 CA076292
T32 CA115308
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Wed, 04 Jan 2017, 00:38:43 EST by Susan Allen on behalf of Institute for Molecular Bioscience