Genomic and transcriptomic determinants of clinical outcomes in patients with AML and DNMT3A mutations

Genomic and transcriptomic determinants of clinical outcomes in patients with AML and DNMT3A mutations

Abstract Acute myeloid leukemia (AML) and DNMT3A mutations (DNMT3A mut) are considered to carry intermediate risk under the 2022 European LeukemiaNet (ELN-2022) classification in the absence of other co-mutations or cytogenetic abnormalities. However, this group is highly heterogeneous. In this stud...

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Main Authors: Sao-Chih Ni, 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, Feng-Ming Tien, Wen-Chien Chou, Hsin-An Hou, Hwei-Fang Tien
Format: Article
Language:English
Published: Nature Publishing Group 2025-05-01
Series:Blood Cancer Journal
Online Access:https://doi.org/10.1038/s41408-025-01287-9
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Summary:Abstract Acute myeloid leukemia (AML) and DNMT3A mutations (DNMT3A mut) are considered to carry intermediate risk under the 2022 European LeukemiaNet (ELN-2022) classification in the absence of other co-mutations or cytogenetic abnormalities. However, this group is highly heterogeneous. In this study, the genomic and transcriptomic features influencing outcomes in DNMT3A-mutated AML were examined in a cohort of 884 patients with AML receiving standard chemotherapy. Stratification by NPM1 and FLT3-ITD status revealed worse survival among patients with NPM1 mutations and wild-type FLT3-ITD (NPM1 mut/FLT3-ITDwt) than patients in the ELN-2022 favorable risk group. The other three subgroups (NPM1 mut/FLT3-ITDmut, NPM1 wt/FLT3-ITDmut, and NPM1 wt/FLT3-ITDwt) exhibited worse prognoses than patients in the ELN-2022 intermediate risk group. Additionally, the presence of TET2 mut in patients with AML and DNMT3A mut/NPM1 mut/FLT3-ITDwt led to reclassification from favorable risk to intermediate risk in the ELN-2022. RNA-sequencing analysis revealed a distinct transcriptomic profile in patients with TET2 mut, highlighting the enrichment of leukemic stem cell signatures and dendritic cell migration, with MMP14, CD200, and CT45A5 identified as key differentially expressed genes. In conclusion, co-mutation patterns strongly affected AML outcomes in patients with DNMT3A mut. Patients with TET2 mut constituted a unique subgroup within the ELN-2022 favorable DNMT3A mut/NPM1 mut/FLT3-ITDwt group, characterized by distinct transcriptomic features and an unfavorable prognosis.
ISSN:2044-5385

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