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 patterns 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. Concurrent WT1 or DNMT3A mutations significantly predicted worse survival in AML patients with CEBPAbZIP-inf. 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, concurrent WT1 or DNMT3A mutations and a dysregulated immune and metabolic state were correlated with poor survival in patients with CEBPAbZIP-inf, and upfront allogeneic transplantation may be indicated for better long-term disease control.
伴CEBPA bZIP框内突变的急性髓系白血病（CEBPAbZIP-inf）在2022年欧洲白血病网（ELN-2022）风险分层中被归入良好预后组，但该类患者仍存在临床结局异质性。本研究旨在探索与CEBPAbZIP-inf患者不良预后相关的突变谱和转录组特征。在887例接受强化化疗的AML患者队列中，共鉴定出113例CEBPAbZIP-inf患者。研究发现，同时存在WT1或DNMT3A突变可显著预测CEBPAbZIP-inf患者更差的生存结局。RNA测序分析显示，无事件生存期较短的患者群体中，干扰素信号通路和代谢通路显著富集。这些患者干扰素刺激基因（IRF2、IRF5、OAS2和IFI35）表达更高，线粒体复合物I（NDUFA12和NDUFB6）及复合物V（ATP5PB和ATP5IF1）相关基因过表达与不良生存显著相关，该结果在TARGET AML队列中得到独立验证。结论表明，WT1或DNMT3A共存突变及免疫代谢状态失调与CEBPAbZIP-inf患者不良预后相关，早期进行异基因造血干细胞移植可能有助于获得更好的长期疾病控制。
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