Key Points IFN-γ primes the NOD2 pathway in AML, increasing susceptibility to MTP-PE. MTP-PE plus IFN-γ induces AML blast apoptosis via caspase-1. MTP-PE plus IFN-γ matures and activates disease-suppressed NK cells. TLRs, a family of membrane-bound pattern recognition receptors found on innate immune cells, have been well studied in the context of cancer therapy. Activation of these receptors has been shown to induce inflammatory anticancer events, including differentiation and apoptosis, across a wide variety of malignancies. In contrast, intracellular pattern recognition receptors such as NOD-like receptors have been minimally studied. NOD2 is a member of the NOD-like receptor family that initiates inflammatory signaling in response to the bacterial motif muramyl dipeptide. In this study, we examined the influence of NOD2 in human acute myeloid leukemia (AML) cells, demonstrating that IFN-γ treatment upregulated the expression of NOD2 signaling pathway members SLC15A3 and SLC15A4, downstream signaling kinase RIPK2, and the NOD2 receptor itself. This priming allowed for effective induction of caspase-1–dependent cell death upon treatment with muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic ligand for NOD2. Furthermore, the combination of MTP-PE and IFN-γ on AML blasts generated an inflammatory cytokine profile and activated NK cells. In a murine model of AML, dual treatment with MTP-PE and IFN-γ led to a significant increase in mature CD27− CD11b+ NK cells as well as a significant reduction in disease burden and extended survival. These results suggest that NOD2 activation, primed by IFN-γ, may provide a novel therapeutic option for AML.

中文翻译：

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细胞内模式识别受体 NOD2 的激活促进急性髓性白血病 (AML) 细胞凋亡并在 AML 动物模型中提供生存优势

要点 IFN-γ 引发 AML 中的 NOD2 通路，增加对 MTP-PE 的易感性。MTP-PE 加 IFN-γ 通过 caspase-1 诱导 AML 母细胞凋亡。MTP-PE 加 IFN-γ 成熟并激活疾病抑制的 NK 细胞。TLRs 是在先天免疫细胞上发现的膜结合模式识别受体家族，在癌症治疗的背景下已经得到了很好的研究。这些受体的激活已被证明可以在多种恶性肿瘤中诱导炎症性抗癌事件，包括分化和细胞凋亡。相比之下，对细胞内模式识别受体（如 NOD 样受体）的研究很少。NOD2 是 NOD 样受体家族的成员，它启动炎症信号以响应细菌基序胞壁酰二肽。在这项研究中，我们检查了 NOD2 在人急性髓性白血病 (AML) 细胞中的影响，证明 IFN-γ 治疗上调了 NOD2 信号通路成员 SLC15A3 和 SLC15A4、下游信号激酶 RIPK2 和 NOD2 受体本身的表达。这种引发允许在用 NOD2 的合成配体壁酰三肽磷脂酰乙醇胺 (MTP-PE) 处理后有效诱导 caspase-1 依赖性细胞死亡。此外，MTP-PE 和 IFN-γ 对 AML 母细胞的组合产生炎性细胞因子谱并激活 NK 细胞。在 AML 小鼠模型中，MTP-PE 和 IFN-γ 双重治疗导致成熟 CD27-CD11b+ NK 细胞显着增加，疾病负担显着降低，生存期延长。这些结果表明，由 IFN-γ 引发的 NOD2 激活，