STING在RUNX1::RUNX1T1白血病细胞存活中的关键作用

STING is crucial for the survival of RUNX1::RUNX1T1 leukemia cells

LEUKEMIA

影响因子:13.4

分区:医学1区 Top / 血液学1区肿瘤学2区

发表日期:2024 Oct

作者: Yue Sun, Yushuang Wu, Guozheng Pang, Jingru Huang, Mengyao Sheng, Jiaying Xie, Pingyue Chen, Yin Wang, Dongrui Yin, Guangjie Zhao, Stefan K Bohlander, Jian Huang, Guo-Liang Xu, Hai Gao, Dan Zhou, Yuheng Shi

DOI: 10.1038/s41375-024-02383-8

摘要

尽管携带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%的患者在2.5年内复发并对后续化疗产生耐药性[1]。因此，识别新的治疗靶点以改善AE白血病的治疗效果势在必行。在本研究中，我们揭示靶向STING能有效抑制AE白血病细胞的生长。基因和药理学抑制STING均可减少AE白血病细胞的数量。重要的是，在小鼠原代AE白血病模型中，STING的缺失显著减缓白血病发生并延长动物寿命。阻断STING的下游炎症通路产生与STING抑制类似的效果，突出STING依赖的炎症反应在维持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，我们鉴定出脂肪酸去饱和酶2（FADS2）作为STING抑制的非经典下游因子，介导细胞死亡。抑制STING释放FADS2活性，诱导多不饱和脂肪酸（PUFAs）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，并提示STING可能成为临床干预的潜在治疗靶点。

Abstract

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.