Department of Pediatrics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China.
J Transl Med. 2023 Sep 7;21(1):606. doi: 10.1186/s12967-023-04481-0.
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.
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.
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.
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.
B 细胞淋巴瘤 2（Bcl-2）作为治疗靶点的鉴定导致了急性髓细胞白血病（AML）治疗的范式转变。细胞焦亡是一种新的抗肿瘤治疗机制，因其具有细胞毒性和免疫原性作用。维奈托克联合低甲基化剂（HMAs）已被证明可导致 AML 患者获得持久缓解并显著改善预后。然而，我们对这种联合作用的机制的理解还在不断发展。
我们研究了 Bcl-2 抑制剂维奈托克是否诱导 AML 细胞发生细胞焦亡，并确定了细胞焦亡效应蛋白。通过 Western blot、免疫沉淀、RNA 干扰、CCK8 检测和 LDH 检测，我们探讨了细胞焦亡效应的机制。研究了细胞焦亡效应蛋白 GSDME 的表达与 AML 预后的关系。在小鼠模型和临床样本中，研究并证实了 GSDME 去甲基化联合维奈托克治疗对细胞焦亡的影响。
维奈托克诱导的细胞焦亡是通过 caspase-3 依赖性 GSDME 切割介导的。机制上，维奈托克通过激活内在凋亡途径上调 caspase-3 和 GSDME 切割。基于公共数据库和患者样本分析，发现 AML 中 GSDME 启动子甲基化导致 GSDME 下调，低 GSDME 表达与预后不良显著相关。体内和体外实验表明，GSDME 过表达或 HMAs 介导的 GSDME 表达恢复可显著增加 AML 中维奈托克诱导的细胞焦亡。
GSDME 介导的细胞焦亡可能是 Bcl-2 抑制剂抗白血病作用的一个新方面。这一发现为潜在的生物标志物和治疗策略提供了新的思路，确定了一个重要的机制，解释了维奈托克和 HMAs 在 AML 中的临床活性。
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