■急性髓性白血病(AML)是一种侵袭性血癌,异质性高,预后差。尽管烟酰胺腺嘌呤二核苷酸(NAD)的代谢重编程已被报道在急性髓细胞性白血病(AML)的发病机制中起关键作用。NAD代谢的预后价值及其与AML免疫微环境的相关性尚不清楚.
■我们利用我们对655例AML患者和NAD代谢相关基因的大规模RNA-seq数据,基于稀疏回归分析建立预后NAD代谢评分。该签名在三个独立的数据集上进行了验证,包括总共1,215名AML患者。采用ssGSEA和ESTIMATE算法解剖肿瘤免疫微环境。进行离体药物筛选和体外实验验证,以确定高危患者的潜在治疗方法。采用体外敲低和功能实验来研究SLC25A51的作用,SLC25A51是一种与签名有关的线粒体NAD转运蛋白基因。
■产生了8基因NAD代谢标签(NADM8),并在1,800多名AML患者中显示出强大的预后价值。高NADM8评分可以有效区分具有不良临床特征和遗传病变的AML患者,并作为预测预后不良的独立因素。免疫微环境分析显示,在NADM8评分较高的患者中,明显富集了不同的肿瘤浸润免疫细胞,并激活了免疫检查点。作为AML免疫反应评估的潜在生物标志物。此外,在一组9个AML细胞系中进行体外药物筛选和体外实验验证表明,NADM8评分高的患者对PI3K抑制剂更敏感,GDC-0914.最后,功能实验也证实了SLC25A51在AML中的关键致病作用,这可能是一个有希望的治疗目标。
我们的研究表明,与NAD代谢相关的特征可以促进AML的风险分层和预后预测,并指导包括免疫治疗和靶向治疗在内的治疗决策。
UNASSIGNED: Acute myeloid leukemia (AML) is an aggressive blood cancer with high heterogeneity and poor prognosis. Although the metabolic reprogramming of nicotinamide adenine dinucleotide (NAD) has been reported to play a pivotal role in the pathogenesis of acute myeloid leukemia (AML), the prognostic value of NAD metabolism and its correlation with the immune microenvironment in AML remains unclear.
UNASSIGNED: We utilized our large-scale RNA-seq data on 655 patients with AML and the NAD metabolism-related genes to establish a prognostic NAD metabolism score based on the sparse regression analysis. The signature was validated across three independent datasets including a total of 1,215 AML patients. ssGSEA and ESTIMATE algorithms were employed to dissect the tumor immune microenvironment. Ex vivo drug screening and in vitro experimental validation were performed to identify potential therapeutic approaches for the high-risk patients. In vitro knockdown and functional experiments were employed to investigate the role of SLC25A51, a mitochondrial NAD+ transporter gene implicated in the signature.
UNASSIGNED: An 8-gene NAD metabolism signature (NADM8) was generated and demonstrated a robust prognostic value in more than 1,800 patients with AML. High NADM8 score could efficiently discriminate AML patients with adverse clinical characteristics and genetic lesions and serve as an independent factor predicting a poor prognosis. Immune microenvironment analysis revealed significant enrichment of distinct tumor-infiltrating immune cells and activation of immune checkpoints in patients with high NADM8 scores, acting as a potential biomarker for immune response evaluation in AML. Furthermore, ex vivo drug screening and in vitro experimental validation in a panel of 9 AML cell lines demonstrated that the patients with high NADM8 scores were more sensitive to the PI3K inhibitor, GDC-0914. Finally, functional experiments also substantiated the critical pathogenic role of the SLC25A51 in AML, which could be a promising therapeutic target.
UNASSIGNED: Our study demonstrated that NAD metabolism-related signature can facilitate risk stratification and prognosis prediction in AML and guide therapeutic decisions including both immunotherapy and targeted therapies.