Acute myeloid leukemia (AML) and DNMT3A mutations (DNMT3Amut) 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 (NPM1mut/FLT3-ITDwt) than patients in the ELN-2022 favorable risk group. The other three subgroups (NPM1mut/FLT3-ITDmut, NPM1wt/FLT3-ITDmut, and NPM1wt/FLT3-ITDwt) exhibited worse prognoses than patients in the ELN-2022 intermediate risk group. Additionally, the presence of TET2mut in patients with AML and DNMT3Amut/NPM1mut/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 TET2mut, 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 DNMT3Amut. Patients with TET2mut constituted a unique subgroup within the ELN-2022 favorable DNMT3Amut/NPM1mut/FLT3-ITDwt group, characterized by distinct transcriptomic features and an unfavorable prognosis.
在2022年欧洲白血病网（ELN-2022）分类中，若不伴有其他共突变或细胞遗传学异常，急性髓系白血病（AML）伴DNMT3A突变（DNMT3Amut）被视为中危组，但该群体存在高度异质性。本研究对884例接受标准化疗的AML患者队列进行了分析，探讨了影响DNMT3A突变AML患者预后的基因组与转录组特征。根据NPM1和FLT3-ITD状态分层显示，携带NPM1突变伴FLT3-ITD野生型（NPM1mut/FLT3-ITDwt）的患者生存期较ELN-2022低危组更差。其余三个亚组（NPM1mut/FLT3-ITDmut、NPM1wt/FLT3-ITDmut及NPM1wt/FLT3-ITDwt）的预后均差于ELN-2022中危组患者。此外，在DNMT3Amut/NPM1mut/FLT3-ITDwt的AML患者中，若同时存在TET2突变，其ELN-2022风险分层会从低危重新划分为中危。RNA测序分析显示，TET2突变患者具有独特的转录组特征，主要表现为白血病干细胞特征富集及树突状细胞迁移相关通路上调，其中MMP14、CD200和CT45A5被确定为关键差异表达基因。综上，共突变模式显著影响DNMT3Amut AML患者的预后。在ELN-2022低危组（DNMT3Amut/NPM1mut/FLT3-ITDwt）中，TET2突变患者构成一个独特亚组，其特征表现为特异的转录组学改变及不良预后。
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