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

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

doi:10.1038/s41408-023-00975-8

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

Blood Cancer J. 2024 Jan 23;14(1):15. doi: 10.1038/s41408-023-00975-8.

Authors

Feng-Ming Tien^{1

2}, Chi-Yuan Yao^{1

2

3}, Xavier Cheng-Hong Tsai¹, Min-Yen Lo^{2

4}, Chien-Yuan Chen¹, Wan-Hsuan Lee^{2

5}, Chien-Chin Lin^{1

3}, Yuan-Yeh Kuo⁶, Yen-Ling Peng¹, Mei-Hsuan Tseng⁶, Yu-Sin Wu⁷, Ming-Chih Liu⁸, Liang-In Lin⁹, Ming-Kai Chuang^{1

3}, Bor-Sheng Ko^{1

10}, Ming Yao¹, Jih-Luh Tang^{1

6

10}, Wen-Chien Chou^{1

3}, Hsin-An Hou¹¹, Hwei-Fang Tien^{1

12}

Affiliations

¹ Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
² Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
³ Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁴ Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan.
⁵ Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan.
⁶ Tai-Chen Cell Therapy Center, National Taiwan University, Taipei, Taiwan.
⁷ Department of Nursing, National Taiwan University Cancer Center, Taipei, Taiwan.
⁸ Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
⁹ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹⁰ Department of Hematological Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
¹¹ Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. [email protected].
¹² Department of Internal Medicine, Far-Eastern Memorial Hospital, New Taipei City, Taiwan.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
CCAAT-Enhancer-Binding Proteins / genetics
Gene Expression Profiling
Humans
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / therapy
Metabolic Networks and Pathways
Mutation
NADPH Dehydrogenase
Progression-Free Survival

Substances

CEBPA protein, human
CCAAT-Enhancer-Binding Proteins
NDUFA12 protein, human
NADPH Dehydrogenase