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Antileukemic effect of venetoclax and hypomethylating agents via caspase-3/GSDME-mediated pyroptosis
Fanghua Ye1, Wen Zhang1, Chenying Fan1
1Department of Pediatrics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China.
Background:
The identifying of B-cell lymphoma 2 (Bcl-2) as a therapeutic target has led to a paradigm shift in acute myeloid leukemia (AML) treatment. Pyroptosis is a novel antitumor therapeutic mechanism due to its cytotoxic and immunogenic effects. The combination of venetoclax and hypomethylating agents (HMAs) has been shown to lead to durable responses and significantly improve prognosis in patients with AML. However, our understanding of the mechanisms underlying this combinatorial activity is evolving.
Methods:
We investigated whether the Bcl-2 inhibitor venetoclax induces AML cell pyroptosis and identified pyroptosis effector proteins. Via using western blotting, immunoprecipitation, RNA interference, CCK8 assays, and LDH assays, we explored the mechanism underlying the pyroptotic effect. The relationship between the expression of the pyroptosis effector protein GSDME and AML prognosis was investigated. The effect of GSDME demethylation combined with venetoclax treatment on pyroptosis was investigated and confirmed in mouse models and clinical samples.
Results:
Venetoclax induces pyroptosis that is mediated by caspase-3-dependent GSDME cleavage. Mechanistically, venetoclax upregulates caspase-3 and GSDME cleavage by activating the intrinsic apoptotic pathway. GSDME is downregulated in AML by promoter methylation, and low GSDME expression is significantly associated with poor prognosis, based on public databases and patient sample analysis. In vivo and in vitro experiments showed that GSDME overexpression or HMAs-mediated restoration of GSDME expression significantly increased venetoclax-induced pyroptosis in AML.
Conclusion:
GSDME-mediated pyroptosis may be a novel aspect of the antileukemic effect of Bcl-2 inhibitors. This finding offers new insights into potential biomarkers and therapeutic strategies, identifying an important mechanism explaining the clinical activity of venetoclax and HMAs in AML.
Insights
Venetoclax induces pyroptosis in acute myeloid leukemia (AML) by activating the intrinsic apoptotic pathway, leading to GSDME cleavage. Restoring GSDME expression enhances this anti-leukemic effect, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- B-cell lymphoma 2 (Bcl-2) inhibition represents a significant advancement in acute myeloid leukemia (AML) treatment.
- Pyroptosis, a form of programmed cell death, offers a novel therapeutic mechanism against cancer due to its cytotoxic and immunogenic properties.
- The combination of venetoclax (a Bcl-2 inhibitor) and hypomethylating agents (HMAs) improves outcomes in AML, but the underlying mechanisms require further elucidation.
Purpose of the Study:
- To investigate if venetoclax induces pyroptosis in AML cells.
- To identify the pyroptosis effector proteins involved in venetoclax-induced cell death.
- To explore the prognostic significance of GSDME in AML and its role in venetoclax treatment response.
Main Methods:
- Utilized western blotting, immunoprecipitation, RNA interference, CCK8, and LDH assays to study pyroptosis mechanisms.
- Analyzed GSDME expression in relation to AML prognosis using public databases and patient samples.
- Investigated the combined effects of GSDME demethylation and venetoclax treatment in preclinical models and clinical samples.
Main Results:
- Venetoclax induces pyroptosis via caspase-3-dependent GSDME cleavage, activated by the intrinsic apoptotic pathway.
- GSDME expression is suppressed in AML by promoter methylation, and low GSDME levels correlate with poor prognosis.
- Overexpression or HMA-mediated restoration of GSDME potentiates venetoclax-induced pyroptosis in AML.
Conclusions:
- GSDME-mediated pyroptosis is a key mechanism underlying the antileukemic activity of Bcl-2 inhibitors like venetoclax.
- This finding identifies GSDME as a potential therapeutic target and biomarker for AML.
- The results provide mechanistic insights into the efficacy of venetoclax and HMAs in AML treatment.
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