TY - UNPB
T1 - The NLRP3/eIF2 axis drives cell cycle progression in acute myeloid leukemia
AU - Luciano, Michela
AU - Blöchl, Constantin
AU - Vetter, Julia
AU - Urwanisch, Laura
AU - Neuper, Theresa
AU - Elmer, Dominik P.
AU - Bauer, Renate
AU - Dang, Hieu-Hoa
AU - Strandt, Helen
AU - Neureiter, Daniel
AU - Krenn, Peter
AU - Tesanovic, Suzana
AU - Rieser, Sebastian
AU - Bergsleitner, Olivia
AU - Zell, Lukas
AU - Binder, Stephanie
AU - Schaller, Susanne
AU - Strunk, Dirk
AU - Pleyer, Lisa
AU - Greil, Richard
AU - Winkler, Stephan
AU - Hartmann, Tanja N.
AU - Huber, Christian G.
AU - Aberger, Fritz
AU - Horejs-Hoeck, Jutta
N1 - Authors retain copyright and choose from several distribution/reuse options under which to make the article available (CC BY, CC BY-NC, CC BY-ND, CC BY-NC-ND, CC0, or no reuse).
PY - 2021/6/25
Y1 - 2021/6/25
N2 - Aberrant activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome mediates numerous inflammatory diseases. Oncogenes can activate the NLRP3 inflammasome and thereby promote myeloproliferative neoplasia, suggesting a crucial role of NLRP3 in the malignant transformation of hematopoietic cells. Here, we show that bone marrow-derived mononuclear cells of AML patients display enhanced expression of NLRP3, IL-1{beta}; and IL-18 and that high-level expression of NLRP3 is linked to poor survival of AML patients. Pharmacological and genetic inhibition of NLRP3 inflammasome activation attenuated cell proliferation of MOLM-13 AML cells in vitro. In vivo, genetic inhibition of NLRP3 in MOLM-13 AML cells resulted in reduced engraftment potential in xenografts, along with reduced splenomegaly and organ infiltration. Differential proteomic analysis revealed the eIF2 pathway as potential target of NLRP3 in AML, with a significant increase of eIF2; phosphorylation upon NLRP3 inhibition. NLRP3 inhibition also caused a strong decrease in cyclin - dependent kinases CDK4 and CDK6, accompanied by an upregulation of the CDK inhibitor p21 (CDKN1A) and a marked arrest of cell cycle progression in the G0/G1 phase, consistent with the role of eIF2; phosphorylation as negative cell cycle regulator. Taken together, we show that inhibition of the NLRP3 inflammasome reduces AML cell proliferation by promoting eIF2; phosphorylation, which in turn enhances the expression of cell cycle arrest genes such as p21. Thus, the study uncovers the NLRP3/eIF2 axis as new driver of AML proliferation and proposes a novel therapeutic treatment of AML by targeted inhibition of NLRP3 activation.
AB - Aberrant activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome mediates numerous inflammatory diseases. Oncogenes can activate the NLRP3 inflammasome and thereby promote myeloproliferative neoplasia, suggesting a crucial role of NLRP3 in the malignant transformation of hematopoietic cells. Here, we show that bone marrow-derived mononuclear cells of AML patients display enhanced expression of NLRP3, IL-1{beta}; and IL-18 and that high-level expression of NLRP3 is linked to poor survival of AML patients. Pharmacological and genetic inhibition of NLRP3 inflammasome activation attenuated cell proliferation of MOLM-13 AML cells in vitro. In vivo, genetic inhibition of NLRP3 in MOLM-13 AML cells resulted in reduced engraftment potential in xenografts, along with reduced splenomegaly and organ infiltration. Differential proteomic analysis revealed the eIF2 pathway as potential target of NLRP3 in AML, with a significant increase of eIF2; phosphorylation upon NLRP3 inhibition. NLRP3 inhibition also caused a strong decrease in cyclin - dependent kinases CDK4 and CDK6, accompanied by an upregulation of the CDK inhibitor p21 (CDKN1A) and a marked arrest of cell cycle progression in the G0/G1 phase, consistent with the role of eIF2; phosphorylation as negative cell cycle regulator. Taken together, we show that inhibition of the NLRP3 inflammasome reduces AML cell proliferation by promoting eIF2; phosphorylation, which in turn enhances the expression of cell cycle arrest genes such as p21. Thus, the study uncovers the NLRP3/eIF2 axis as new driver of AML proliferation and proposes a novel therapeutic treatment of AML by targeted inhibition of NLRP3 activation.
KW - immunology
U2 - 10.1101/2021.06.25.449862
DO - 10.1101/2021.06.25.449862
M3 - Preprint
T3 - bioRxiv
BT - The NLRP3/eIF2 axis drives cell cycle progression in acute myeloid leukemia
ER -