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Nucleoporin 98 rearrangements (NUP98re) occur in a wide range of hematologic malignancies including acute leukemias with a variety of fusion partners. NUP98re is associated with adverse prognosis, especially in children. We aimed to better understand the genomics of acute leukemias with NUP98re including fusion partners and co-occurring genomic alterations (GA). Results from 5905 patients with acute leukemia undergoing standard-of-care next generation sequencing on FoundationOneHeme were included for analysis. A total of 78 (1.3%) patient samples harbored NUP98re with a median age of 19 years compared with 62 years for the cases with no NUP98 rearrangement (NUP98wt) (p < 0.001). Patients with NUP98re were more frequently of admixed American ancestry (p < 0.001). Among patients with acute myeloid leukemia, individual genomic alterations more frequently identified in NUP98re cases included WT1 (77% vs. 11%, p < 0.001) and FLT3 (49% vs. 26%, p < 0.001); Alterations more frequent in the NUP98wt cohort included NPM1, KMT2A, TET2, DNMT3A, ASXL1, SRSF2, STAG2, and BCOR (all p < 0.05). NUP98re are rare in patients with acute leukemia, more frequent in pediatrics and younger adults but distributed across all age groups. NUP98re is associated with a unique genomic landscape featuring increased frequencies of mutations with proliferative features (FLT3 and KRAS) and growth suppression (WT1). Alterations in WT1 had the highest co-occurrence rate in samples containing NUP98re. This work highlights the unique GA associated with NUP98 and emphasizes the need for clinical studies to reveal underlying biologic mechanisms and enhance optimal management in the presence of potentially targetable alterations such as NUP98re.