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Fms‐like tyrosine kinase 3 (  FLT 3 ) internal tandem duplication ( ITD ) mutations, common in pediatric acute myeloid leukemia ( AML ), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in   FLT 3 ‐ ITD +  AML . Using  RNA  sequencing and a next‐generation targeted gene panel, we broadly characterize the co‐occurring genomic alterations in pediatric cytogenetically normal ( CN )   FLT 3 ‐ ITD +  AML  to gain a deeper understanding of the clonal patterns and heterogeneity at diagnosis and relapse. We show that chimeric transcripts were present in 21 of 34 (62%) of  de novo  samples, 2 (6%) of these samples included a rare reoccurring fusion partner   BCL 11B . At diagnosis, the median number of mutations other than  FLT 3 per patient was 1 (range 0–3), which involved 8 gene pathways;   WT 1  and   NPM 1  mutations were frequently observed (35% and 24%, respectively). Fusion transcripts and high variant allele frequency ( VAF ) mutants, which included   WT 1 ,   NPM 1 ,   SMARCA 2 ,   RAD 21 , and   TYK 2 , were retained from diagnosis to relapse. We did observe reduction in  VAF  of simple or single mutation clones, but  VAF s were preserved or expanded in more complex clones with multiple mutations. Our data provide the first insight into the genomic complexity of pediatric  CN    FLT 3 ‐ ITD +  AML  and could help stratify future targeted treatment strategies.

Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT 3‐ ITD AML