Normal karyotype acute myeloid leukemia (NK-AML) constitutes 20-25% of pediatric AML and detailed molecular analysis is essential to unravel the genetic background of this group. Using publicly available sequencing data from the TARGET-AML initiative, we investigated the mutational landscape of NK-AML in comparison with abnormal karyotype AML (AK-AML). In 164 (97.6%) of 168 independent NK-AML samples, at least one somatic protein-coding mutation was identified using whole-genome or targeted capture sequencing. We identified a unique mutational landscape of NK-AML characterized by a higher prevalence of mutated , , , , , , and and a lower prevalence of mutated , , and compared with AK-AML. Mutated often co-occurred with mutated , whereas mutated co-occurred with mutated and . In multivariate regression analysis, we identified younger age, WBC count ≥50 × 10/L, -internal tandem duplications, and mutated as independent predictors of adverse prognosis and mutated and as independent predictors of favorable prognosis in NK-AML. In conclusion, NK-AML in children is characterized by a unique mutational landscape which impacts the disease outcome.
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