Targeting NLRP3 inhibits AML progression by inducing PERK/eIF2-mediated apoptosis.
Acute myeloid leukemia
Apoptosis
PERK
eIF2α, NLRP3
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
02 Sep 2024
02 Sep 2024
Historique:
received:
07
03
2024
accepted:
06
08
2024
medline:
3
9
2024
pubmed:
3
9
2024
entrez:
2
9
2024
Statut:
epublish
Résumé
Acute myeloid leukemia (AML) is characterized by the abnormal proliferation of myeloid precursor cells and presents significant challenges in treatment due to its heterogeneity. Recently, the NLRP3 inflammasome has emerged as a potential contributor to AML pathogenesis, although its precise mechanisms remain poorly understood. Public genome datasets were utilized to evaluate the expression of NLRP3 inflammasome-related genes (IL-1β, IL-18, ASC, and NLRP3) in AML patients compared to healthy individuals. CRISPR/Cas9 technology was employed to generate NLRP3-deficient MOLM-13 AML cells, followed by comprehensive characterization using real-time PCR, western blotting, FACS analysis, and transmission electron and immunofluorescence microscopy. Proteomic analyses were conducted to identify NLRP3-dependent alterations in protein levels, with a focus on the eIF2 kinase PERK-mediated signaling pathways. Additionally, in vivo studies were performed using a leukemic mouse model to elucidate the pathogenic role of NLRP3 in AML. Elevated expression of NLRP3 was significantly associated with diminished overall survival in AML patients. Genetic deletion, pharmacological inhibition and silencing by RNA interference of NLRP3 led to decreased AML cell survival through the induction of apoptosis. Proteomic analyses uncovered NLRP3-dependent alterations in protein translation, characterized by enhanced eIF2α phosphorylation in NLRP3-deficient AML cells. Moreover, inhibition of PERK-mediated eIF2α phosphorylation reduced apoptosis by downregulating pro-apoptotic Bcl-2 family members. In vivo studies demonstrated reduced leukemic burden in mice engrafted with NLRP3 knockout AML cells, as evidenced by alleviated leukemic symptoms. Our findings elucidate the involvement of the NLRP3/PERK/eIF2 axis as a novel driver of AML cell survival. Targeting NLRP3-induced signaling pathways, particularly through the PERK/eIF2 axis, presents a promising therapeutic strategy for AML intervention. These insights into the role of the NLRP3 inflammasome offer potential avenues for improving the prognosis and treatment outcomes of AML patients.
Sections du résumé
BACKGROUND
BACKGROUND
Acute myeloid leukemia (AML) is characterized by the abnormal proliferation of myeloid precursor cells and presents significant challenges in treatment due to its heterogeneity. Recently, the NLRP3 inflammasome has emerged as a potential contributor to AML pathogenesis, although its precise mechanisms remain poorly understood.
METHODS
METHODS
Public genome datasets were utilized to evaluate the expression of NLRP3 inflammasome-related genes (IL-1β, IL-18, ASC, and NLRP3) in AML patients compared to healthy individuals. CRISPR/Cas9 technology was employed to generate NLRP3-deficient MOLM-13 AML cells, followed by comprehensive characterization using real-time PCR, western blotting, FACS analysis, and transmission electron and immunofluorescence microscopy. Proteomic analyses were conducted to identify NLRP3-dependent alterations in protein levels, with a focus on the eIF2 kinase PERK-mediated signaling pathways. Additionally, in vivo studies were performed using a leukemic mouse model to elucidate the pathogenic role of NLRP3 in AML.
RESULTS
RESULTS
Elevated expression of NLRP3 was significantly associated with diminished overall survival in AML patients. Genetic deletion, pharmacological inhibition and silencing by RNA interference of NLRP3 led to decreased AML cell survival through the induction of apoptosis. Proteomic analyses uncovered NLRP3-dependent alterations in protein translation, characterized by enhanced eIF2α phosphorylation in NLRP3-deficient AML cells. Moreover, inhibition of PERK-mediated eIF2α phosphorylation reduced apoptosis by downregulating pro-apoptotic Bcl-2 family members. In vivo studies demonstrated reduced leukemic burden in mice engrafted with NLRP3 knockout AML cells, as evidenced by alleviated leukemic symptoms.
CONCLUSION
CONCLUSIONS
Our findings elucidate the involvement of the NLRP3/PERK/eIF2 axis as a novel driver of AML cell survival. Targeting NLRP3-induced signaling pathways, particularly through the PERK/eIF2 axis, presents a promising therapeutic strategy for AML intervention. These insights into the role of the NLRP3 inflammasome offer potential avenues for improving the prognosis and treatment outcomes of AML patients.
Identifiants
pubmed: 39223663
doi: 10.1186/s12964-024-01777-6
pii: 10.1186/s12964-024-01777-6
doi:
Substances chimiques
NLR Family, Pyrin Domain-Containing 3 Protein
0
Eukaryotic Initiation Factor-2
0
eIF-2 Kinase
EC 2.7.11.1
NLRP3 protein, human
0
Inflammasomes
0
EIF2AK3 protein, human
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
424Subventions
Organisme : Cancer Cluster Salzburg
ID : 20102-P1601064-FPR01-2017
Organisme : Cancer Cluster Salzburg
ID : 20102-F2001080-FPR
Organisme : Cancer Cluster Salzburg
ID : 20102-P1601064-FPR01-2017
Organisme : Cancer Cluster Salzburg
ID : 20102-P1601064-FPR01-2017
Organisme : Cancer Cluster Salzburg
ID : 20102-P1601064-FPR01-2017
Organisme : Cancer Cluster Salzburg
ID : 20102-P1601064-FPR01-2017
Organisme : Cancer Cluster Salzburg
ID : 20102-P1601064-FPR01-2017
Organisme : Cancer Cluster Salzburg
ID : 20102-P1601064-FPR01-2017
Organisme : Austrian Science Fund
ID : P33969
Organisme : Austrian Science Fund
ID : P33969
Organisme : Austrian Science Fund
ID : W1213
Organisme : Austrian Science Fund
ID : P33969
Organisme : Austrian Science Fund
ID : W1213
Organisme : Austrian Science Fund
ID : W1213
Organisme : Austrian Science Fund
ID : W1213
Organisme : Austrian Science Fund
ID : W1213
Organisme : Austrian Science Fund
ID : W1213
Organisme : Austrian Science Fund
ID : W1213
Organisme : Austrian Science Fund
ID : P33969
Organisme : Interreg
ID : ITAT1054
Organisme : Interreg
ID : ITAT1054
Organisme : Interreg
ID : ITAT1054
Organisme : Interreg
ID : ITAT1054
Organisme : Interreg
ID : ITAT1054
Organisme : Interreg
ID : ITAT1054
Organisme : Salzburger Landesregierung
ID : 20102-F1901165-KZP
Organisme : Salzburger Landesregierung
ID : 20102-F1901165-KZP
Organisme : Salzburger Landesregierung
ID : 20102-F1901165-KZP
Organisme : Jose Carreras
ID : DJCLS 04 R/2020
Informations de copyright
© 2024. The Author(s).
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