尽管具有 RUNX1::RUNX1T1 (AE) 融合的急性髓系白血病 (AML) 患者预后相对较好，但约 50% 的患者会在 2.5 年内复发并对后续化疗产生耐药性 [1]。因此，必须确定 AE 白血病的新治疗靶点以改善预后。在这项研究中，我们发现靶向 STING 可有效抑制 AE 白血病细胞的生长。 STING 的遗传和药理学抑制都会导致 AE 白血病细胞的减少。重要的是，在小鼠原发性 AE 白血病模型中，STING 缺失显着减弱了白血病的发生并延长了动物的寿命。阻断 STING 的下游炎症通路会产生与 AE 白血病细胞中 STING 抑制相似的效果，凸显了 STING 依赖性炎症反应在维持 AE 白血病细胞存活中的关键作用。此外，通过全基因组 CRISPR 筛选，我们发现脂肪酸去饱和酶 2 (FADS2) 是介导细胞死亡的 STING 抑制下游的非典型因子。抑制 STING 会释放 FADS2 活性，从而诱导多不饱和脂肪酸 (PUFA) 的合成并引发脂质过氧化相关的细胞死亡 [2]。总而言之，这些发现揭示了 STING 在 AE 阳性 AML 细胞存活中的关键功能，并表明 STING 是这些患者临床干预的潜在治疗靶标。© 2024。作者获得 Springer 独家许可自然有限公司。

Even though acute myeloid leukemia (AML) patients with a RUNX1::RUNX1T1 (AE) fusion have a relatively favorable prognosis, approximately 50% relapse within 2.5 years and develop resistance to subsequent chemotherapy [1]. It is therefore imperative to identify novel therapeutic targets for AE leukemia to improve outcomes. In this study, we unveil that targeting STING effectively suppresses the growth of AE leukemia cells. Both genetic and pharmacological inhibition of STING lead to the diminish of AE leukemia cells. Importantly, in a mouse primary AE leukemia model, STING deletion significantly attenuates leukemogenesis and prolongs the animals' lifespan. Blocking the downstream inflammatory pathway of STING yields similar effects to STING inhibition in AE leukemia cells, highlighting the pivotal role of STING-dependent inflammatory responses in sustaining the survival of AE leukemia cells. Moreover, through a genome-wide CRISPR screen, we identified fatty acid desaturase 2 (FADS2) as a non-canonical factor downstream of STING inhibition that mediates cell death. Inhibition of STING releases FADS2 activity, consequently inducing the synthesis of polyunsaturated fatty acids (PUFAs) and triggering lipid peroxidation-associated cell death [2]. Taken together, these findings reveal a critical function of STING in the survival of AE-positive AML cells and suggest STING to be a potential therapeutic target for clinical intervention in these patients.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.