刺激对于runx1 :: runx1t1白血病细胞的存活至关重要
STING is crucial for the survival of RUNX1::RUNX1T1 leukemia cells
影响因子:13.40000
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
摘要
即使患有RUNX1 :: RUNX1T1（AE）融合的急性髓样白血病（AML）患者的预后相对较好，但在2.5年内大约50％复发，并发展出对随后的化疗的抗药性[1]。因此，必须确定AE白血病改善预后的新型治疗靶标。在这项研究中，我们揭示了针对刺激的靶向有效抑制AE白血病细胞的生长。遗传和药理抑制刺激导致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缺失显着减轻了白血病的形成并延长了动物的寿命。阻塞刺激的下游炎症途径与AE白血病细胞中的刺激性抑制相似，突出了依赖于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，我们将脂肪酸去饱和酶2（FADS2）鉴定为介导细胞死亡的sting抑制下游的一种非经典因子。抑制刺激性释放FADS2活性，因此诱导多不饱和脂肪酸（PUFAS）的合成并触发与脂质过氧化相关的细胞死亡[2]。综上所述，这些发现揭示了刺痛在AE阳性AML细胞存活中的关键功能，并认为STING是这些患者临床干预的潜在治疗靶标。
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.