Work

Distinct clinical and molecular profiles of acute myeloid leukemia defined by mutations in IDH1, IDH2, and TET2

Year: 2026

Type: article

Abstract: Acute myeloid leukemia (AML) is a heterogeneous disease driven by recurring somatic mutations, frequently affecting genes involved in epigenetic regulation. Mutations in IDH1, IDH2, and TET2 are largely mutually exclusive and thought to converge on a shared pathway by impairing TET-mediated DNA demethylation, either directly through loss of TET2 activity or indirectly through the accumulation of the oncometabolite (R)-2-hydroxyglutarate (2-HG) in IDH1- and IDH2-mutant AML. Whether this biochemical convergence translates into similar disease biology remains unclear. Here, we analyzed AML defined by mutations in IDH1, IDH2, or TET2 using population-based data from the Swedish AML Registry, complemented by transcriptomic and 5-hydroxymethylcytosine (5hmC) profiling of purified blasts from a highly selected subset of primary AML samples. TET2-mutant AML occurred at an older age and was associated with a more pronounced thrombocytopenia, whereas IDH1- and IDH2-mutant AML showed deeper neutropenia and more favorable overall survival, including after adjustment for clinical covariates. Transcriptomic and 5hmC alterations showed only modest concordance, with 5hmC profiles providing clearer separation of the mutational subgroups. TET2-mutant samples showed significant enrichment of the oxidative phosphorylation pathway compared with IDH1- and IDH2-mutant AML. The mutational groups also showed distinct closest normal counterparts among healthy hematopoietic cell populations. Together, these findings demonstrate that IDH1, IDH2, and TET2 mutations define clinically and molecularly distinct subgroups of AML, highlighting the relevance of mutation-specific clinical stratification.

Source: Haematologica

DOI: 10.3324/haematol.2026.301319