TY - JOUR
T1 - Targeting NLRP3 inhibits AML progression by inducing PERK/eIF2-mediated apoptosis
AU - Luciano, Michela
AU - Sieberer, Helene
AU - Krenn, Peter W.
AU - Dang, Hieu-Hoa
AU - Vetter, Julia
AU - Neuper, Theresa
AU - Amend, Diana
AU - Bloechl, Constantin
AU - Weichenberger, Christian X.
AU - Eglseer, Anna
AU - Unger, Michael S.
AU - Andosch, Ancuela
AU - Steiner, Philip
AU - Neureiter, Daniel
AU - Bauer, Renate
AU - Hummer, Laura
AU - Tesanovic, Suzana
AU - Binder, Stephanie
AU - Elmer, Dominik P.
AU - Strandt, Helen
AU - Schaller, Susanne
AU - Strunk, Dirk
AU - Pleyer, Lisa
AU - Greil, Richard
AU - Winkler, Stephan
AU - Hartmann, Tanja N.
AU - Schmidt-Arras, Dirk
AU - Huber, Christian G.
AU - Aberger, Fritz
AU - Horejs-Hoeck, Jutta
N1 - Neureiter: Institute of Pathology, Paracelsus Medical University (PMU), University Hospital Salzburg (SALK), Salzburg, 5020, Austria; Strunk: Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, 5020, Austria; Pleyer, Greil: 3rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectiology, Oncologic Center, Paracelsus Medical University (PMU), University Hospital Salzburg (SALK), Salzburg, 5020, Austria
PY - 2024/9/2
Y1 - 2024/9/2
N2 - BackgroundAcute 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.MethodsPublic genome datasets were utilized to evaluate the expression of NLRP3 inflammasome-related genes (IL-1 beta, 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.ResultsElevated 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 eIF2 alpha phosphorylation in NLRP3-deficient AML cells. Moreover, inhibition of PERK-mediated eIF2 alpha 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.ConclusionOur 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.
AB - BackgroundAcute 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.MethodsPublic genome datasets were utilized to evaluate the expression of NLRP3 inflammasome-related genes (IL-1 beta, 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.ResultsElevated 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 eIF2 alpha phosphorylation in NLRP3-deficient AML cells. Moreover, inhibition of PERK-mediated eIF2 alpha 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.ConclusionOur 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.
KW - Acute myeloid leukemia
KW - Apoptosis
KW - Perk
KW - eIF2 alpha, NLRP3
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pmu_pure&SrcAuth=WosAPI&KeyUT=WOS:001304124300002&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1186/s12964-024-01777-6
DO - 10.1186/s12964-024-01777-6
M3 - Original Article
C2 - 39223663
SN - 1478-811X
VL - 22
JO - CELL COMMUNICATION AND SIGNALING
JF - CELL COMMUNICATION AND SIGNALING
IS - 1
M1 - 424
ER -