A new genomic framework has been developed to categorize pediatric acute myeloid leukemia (pAML). By analyzing 887 pAML cases using RNA sequencing and genome profiling, researchers identified 23 molecular categories, including new entities such as UBTF and BCL11B, which account for 91.4% of the cohort. These categories are associated with distinct expression profiles and mutational patterns, and are strongly linked to clinical outcomes. The framework includes a new prognostic system based on these categories and minimal residual disease (MRD). This comprehensive framework provides a basis for future classification and treatment strategies for pAML. The study highlights the unique genetic and biological features of pAML, which differ from adult AML. Key findings include the identification of recurrent driver alterations in pAML, such as KMT2A rearrangements, NUP98 fusions, and UBTF tandem duplications. These alterations are associated with distinct clinical outcomes and are categorized into molecular groups based on their genetic and expression profiles. The framework also incorporates HOXA and HOXB gene expression profiles, which define large clusters of pAML cases with similar biological characteristics. The study also examined the clinical outcomes of these molecular categories using two independent cohorts, the COG AAML1031 study and the AML08 study. The results showed strong associations between new molecular categories and clinical outcomes, such as high risk for PICALM::MLLT10, UBTF, and KAT6Ar, and low risk for CBFB-GDXY. These findings support the use of molecular categories and MRD for risk stratification in pAML. The study proposes a new framework for pAML classification that integrates genomic and clinical data, providing a more accurate and comprehensive understanding of pAML. This framework could serve as a basis for future risk stratification and clinical decisions in pAML. The study also emphasizes the importance of next-generation sequencing for accurate diagnosis and treatment of pAML.A new genomic framework has been developed to categorize pediatric acute myeloid leukemia (pAML). By analyzing 887 pAML cases using RNA sequencing and genome profiling, researchers identified 23 molecular categories, including new entities such as UBTF and BCL11B, which account for 91.4% of the cohort. These categories are associated with distinct expression profiles and mutational patterns, and are strongly linked to clinical outcomes. The framework includes a new prognostic system based on these categories and minimal residual disease (MRD). This comprehensive framework provides a basis for future classification and treatment strategies for pAML. The study highlights the unique genetic and biological features of pAML, which differ from adult AML. Key findings include the identification of recurrent driver alterations in pAML, such as KMT2A rearrangements, NUP98 fusions, and UBTF tandem duplications. These alterations are associated with distinct clinical outcomes and are categorized into molecular groups based on their genetic and expression profiles. The framework also incorporates HOXA and HOXB gene expression profiles, which define large clusters of pAML cases with similar biological characteristics. The study also examined the clinical outcomes of these molecular categories using two independent cohorts, the COG AAML1031 study and the AML08 study. The results showed strong associations between new molecular categories and clinical outcomes, such as high risk for PICALM::MLLT10, UBTF, and KAT6Ar, and low risk for CBFB-GDXY. These findings support the use of molecular categories and MRD for risk stratification in pAML. The study proposes a new framework for pAML classification that integrates genomic and clinical data, providing a more accurate and comprehensive understanding of pAML. This framework could serve as a basis for future risk stratification and clinical decisions in pAML. The study also emphasizes the importance of next-generation sequencing for accurate diagnosis and treatment of pAML.