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-ITD(wt)) than patients in the ELN-2022 favorable risk group. The other three subgroups (NPM1(mut)/FLT3-ITD(mut), NPM1(wt)/FLT3-ITD(mut), and NPM1(wt)/FLT3-ITD(wt)) 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-ITD(wt) 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-ITD(wt) group, characterized by distinct transcriptomic features and an unfavorable prognosis.