Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations

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2024年1月23日

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Feng-Ming Tien,
Chi-Yuan Yao,
Xavier Cheng-Hong Tsai,
Min-Yen Lo,
Chien-Yuan Chen,
Wan-Hsuan Lee,
Chien-Chin Lin,
Yuan-Yeh Kuo,
Yen-Ling Peng,
Mei-Hsuan Tseng,
Yu-Sin Wu,
Ming-Chih Liu,
Liang-In Lin,
Ming-Kai Chuang,
Bor-Sheng Ko,
Ming Yao,
Jih-Luh Tang,
Wen-Chien Chou,
Hsin-An Hou,
Hwei-Fang Tien

摘要

Acute myeloid leukemia (AML) with CEBPA bZIP in-frame mutations (CEBPA^bZIP-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 CEBPA^bZIP-inf. One hundred and thirteen CEBPA^bZIP-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 CEBPA^bZIP-inf. RNA-sequencing analysis revealed an enrichment of interferon (IFN) signaling and metabolic pathways in those with a shorter event-free survival (EFS). CEBPA^bZIP-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 CEBPA^bZIP-inf, and upfront allogeneic transplantation may be indicated for better long-term disease control.