Sun Yue, Wu Yushuang, Pang Guozheng, Huang Jingru, Sheng Mengyao, Xie Jiaying, Chen Pingyue, Wang Yin, Yin Dongrui, Zhao Guangjie, Bohlander Stefan K, Huang Jian, Xu Guo-Liang, Gao Hai, Zhou Dan, Shi Yuheng
Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) & Zhongshan-Xuhui Hospital, Medical College of Fudan University, Shanghai, 200032, China.
Huashan Hospital, Fudan University, Shanghai, 200024, China.
Leukemia. 2024 Oct;38(10):2102-2114. doi: 10.1038/s41375-024-02383-8. Epub 2024 Aug 23.
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.
尽管伴有RUNX1::RUNX1T1（AE）融合基因的急性髓系白血病（AML）患者预后相对较好，但仍有大约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，必须为AE白血病确定新的治疗靶点以改善治疗结果。在本研究中，我们发现靶向干扰素基因刺激蛋白（STING）可有效抑制AE白血病细胞的生长。对STING进行基因和药物抑制均会导致AE白血病细胞数量减少。重要的是，在小鼠原发性AE白血病模型中，敲除STING可显著减轻白血病发生并延长动物寿命。阻断STING的下游炎症信号通路在AE白血病细胞中产生的效果与抑制STING相似，这突出了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，我们确定脂肪酸去饱和酶2（FADS2）是STING抑制下游的一个非典型因子，介导细胞死亡。抑制STING可释放FADS2的活性，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]。综上所述，这些发现揭示了STING在AE阳性AML细胞存活中的关键作用，并表明STING可能是这些患者临床干预中的一个潜在治疗靶点。
