Description
The NLR family pyrin domain containing 3 (NLRP3) inflammasome has lately attracted great attention in various biomedical fields, as excessive activation of the NLRP3 inflammasome plays an important role in many different pathologies including hematologic diseases. In this context, our study highlights a novel function of the NLRP3 inflammasome in Acute Myeloid Leukemia (AML). We demonstrate that NLRP3 inflammasome components and the inflammasome-related cytokines IL-18 and IL-1b are highly overexpressed in AML patients, resulting in poor survival rates. In this work, we show that NLRP3 acts as a driver of AML blast survival, as the inhibition of NLRP3 inflammasome activation by CP-456773 reduced AML cell survival in vitro. On the cellular level, NLRP3 inhibition reduced cell proliferation, induced cell cycle arrest, and increased apoptosis in human AML cell lines. Transmission Electron Microscopy (TEM) analysis further confirmed those findings, as clear hallmarks of cell cycle arrest and apoptosis were present in AML cells treated with the NLRP3 inhibitor. In addition, we show a positive correlation between NLRP3 and expression of the oncogenic kinase FLT3. Using shotgun proteomics, we identified that the cell cycle dependent kinase CDK6 is downregulated. This in turn induces a negative feedback loop in the FLT3 signaling cascade, resulting in the downregulation of FLT3 itself and STAT5, which is an essential driver of AML cell proliferation. Finally, the combinatory treatment of FDA-approved FLT3 inhibitors with the NLRP3 inhibitor CP-456773 synergistically enhanced apoptosis only in FLT3 mutated AML cells, while FLT3 wildtype AML cells remained unaffected. Thus, our data suggest that NLRP3 inhibition reduces AML cell survival by downregulation of the FLT3 pathway. This might provide a novel treatment option for FLT3 mutated AML patients.Period | 19 Sept 2023 → 21 Sept 2023 |
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Event title | 15th ÖGMBT Annual Meeting: Life Sciences and cutting-edge technologies |
Event type | Conference |
Location | Salzburg, AustriaShow on map |
Degree of Recognition | International |
Fields of Science and Technology Classification 2012
- 106 Biology