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

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.