Dysregulated Immune and Metabolic Pathways were associated with Poor Survival in Adult Acute Myeloid Leukemia with CEBPA bZIP in-frame Mutations

Acute myeloid leukemia (AML) with CEBPA bZIP in-frame mutations (CEBPAbZIP-inf) is classified within the favorable risk group by the 2022 European LeukemiaNet (ELN-2022). However, heterogeneous clinical outcomes are still observed in these patients. In this study, we aimed to investigate the mutation profiles and transcriptomic pattern associated with poor outcomes in patients with CEBPAbZIP-inf. One hundred and thirteen CEBPAbZIP-inf patients were identified in a cohort of 887 AML patients homogeneously treated with intensive chemotherapy. RNA-sequencing analysis revealed an enrichment of interferon (IFN) signaling and metabolic pathways in those with a shorter event-free survival (EFS). CEBPAbZIP-inf patients with a shorter EFS had higher expression of IFN-stimulated genes (IRF2, IRF5, OAS2, and IFI35). Genes in mitochondrial complexes I (NDUFA12 and NDUFB6) and V (ATP5PB and ATP5IF1) were overexpressed and were associated with poorer survival, and the results were independently validated in the TARGET AML cohort. In conclusion, a dysregulated immune and metabolic state were correlated with poor survival in patients with CEBPAbZIP-inf. Overall design: Comparitive gene expression profiling of RNA-seq data for AML patients with CEBPAbZIP-inf and CEBPA wild-type

携带CEBPA bZIP框内突变（CEBPAbZIP-inf）的急性髓系白血病（Acute myeloid leukemia, AML），依据2022年欧洲白血病网络（European LeukemiaNet, ELN-2022）的分类标准，被归入预后良好风险组。但该类患者的临床结局仍存在显著异质性。本研究旨在探究CEBPAbZIP-inf AML患者中与不良预后相关的突变谱及转录组特征。在887例接受同质化强化疗的AML患者队列中，共鉴定出113例CEBPAbZIP-inf患者。RNA测序（RNA-sequencing）分析显示，无事件生存期（Event-Free Survival, EFS）较短的患者亚组中，干扰素（Interferon, IFN）信号通路与代谢通路存在显著富集。EFS较短的CEBPAbZIP-inf患者的干扰素刺激基因（IRF2、IRF5、OAS2及IFI35）表达水平显著升高。线粒体复合物I（NDUFA12、NDUFB6）与复合物V（ATP5PB、ATP5IF1）的相关基因表达上调，且与更差的生存结局显著相关，该结果在TARGET AML队列中得到了独立验证。综上，失调的免疫与代谢状态与CEBPAbZIP-inf AML患者的不良生存结局密切相关。整体实验设计：对CEBPAbZIP-inf与CEBPA野生型AML患者的RNA测序数据开展对比基因表达谱分析。