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Research
Daoxin Ma
Shandong University Qilu Hospital
Corresponding Author
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Background: NLRP3 inflammasome has been reported to be associated with the pathogenesis of multiple solid tumors. However, the role of NLRP3 inflammasome in acute myeloid leukemia (AML) remains unclear.
Methods: NLRP3 inflammasome expression in AML bone marrow samples was investigated via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays and further determined in a cohort of AML bone marrow via Western blot analysis. Cell proliferation and flow cytometry assays were performed to confirm the roles of NLRP3 in AML proliferation, cell cycle regulation, and apoptosis. A mouse model with up-regulated NLRP3 expression was constructed by lentiviral transfection and a model with down-regulated expression was established by hematopoietic stem cell transplantation.
Results: NLRP3 inflammasome is over-expressed and highly activated in AML bone marrow leukemia cells, which is correlated with poor prognosis. The activation of NLRP3 inflammasome in AML cells promotes leukemia cells proliferation, inhibits apoptosis and increases resistance to chemotherapy, while inactivation of NLRP3 by caspase-1 or NF-κB inhibitor shows leukemia-suppressing effects. Bayesian networks analysis and cell co-culture tests further suggests that NLRP3 inflammasome acts through IL-1β but not IL-18 in AML. Knocking down endogenous IL-1β or anti-IL-1β antibody inhibits leukemia cells whereas IL-1β cytokine enhances leukemia proliferation. In AML murine model, up-regulation of NLRP3 increases the leukemia burden in bone marrow, spleen and liver, and shortens the survival time; furthermore, knocking out NLRP3 inhibits leukemia progression.
Conclusions: Collectively, all these evidences demonstrated that NLRP3 inflammasome promotes AML progression in an IL-1β dependent manner, and targeting NLRP3 inflammasome may provide a novel therapeutic option for AML.
Keywords
inflammasome, NLRP3, IL-1β, acute myeloid leukemia, tumorigenesis
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This is a preprint. It has not completed peer review.
Research
Daoxin Ma
Shandong University Qilu Hospital
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 15 Dec, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: NLRP3 inflammasome has been reported to be associated with the pathogenesis of multiple solid tumors. However, the role of NLRP3 inflammasome in acute myeloid leukemia (AML) remains unclear.
Methods: NLRP3 inflammasome expression in AML bone marrow samples was investigated via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays and further determined in a cohort of AML bone marrow via Western blot analysis. Cell proliferation and flow cytometry assays were performed to confirm the roles of NLRP3 in AML proliferation, cell cycle regulation, and apoptosis. A mouse model with up-regulated NLRP3 expression was constructed by lentiviral transfection and a model with down-regulated expression was established by hematopoietic stem cell transplantation.
Results: NLRP3 inflammasome is over-expressed and highly activated in AML bone marrow leukemia cells, which is correlated with poor prognosis. The activation of NLRP3 inflammasome in AML cells promotes leukemia cells proliferation, inhibits apoptosis and increases resistance to chemotherapy, while inactivation of NLRP3 by caspase-1 or NF-κB inhibitor shows leukemia-suppressing effects. Bayesian networks analysis and cell co-culture tests further suggests that NLRP3 inflammasome acts through IL-1β but not IL-18 in AML. Knocking down endogenous IL-1β or anti-IL-1β antibody inhibits leukemia cells whereas IL-1β cytokine enhances leukemia proliferation. In AML murine model, up-regulation of NLRP3 increases the leukemia burden in bone marrow, spleen and liver, and shortens the survival time; furthermore, knocking out NLRP3 inhibits leukemia progression.
Conclusions: Collectively, all these evidences demonstrated that NLRP3 inflammasome promotes AML progression in an IL-1β dependent manner, and targeting NLRP3 inflammasome may provide a novel therapeutic option for AML.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
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