ArticleModern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc2026
Immunophenotypic, Cytogenetic, and Molecular Characterization of NUP98-Rearranged Pediatric Myeloid Neoplasms.
Article in Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
NUP98 rearrangements (NUP98r) are often cryptic and define a high-risk subgroup of pediatric myeloid neoplasms, predominantly acute myeloid leukemia (AML). Despite their clinical significance, the immunophenotypic signatures that enable early recognition of NUP98r remain incompletely characterized. We retrospectively studied 62 pediatric and young adult patients (aged ≤21 years at diagnosis) with NUP98-rearranged myeloid neoplasms diagnosed from 1994 to 2025. We integrated flow cytometry, morphology, cytogenetics, and molecular data and grouped cases based on fusion partner-NUP98::NSD1 (n = 35), NUP98::KDM5A (n = 12), and other NUP98 fusions (NUP98::X; n = 15)-and flow-defined differentiation patterns. NUP98::NSD1 accounted for 56% of cases and was found in older children, with a median age at diagnosis of 13.2 years. These cases displayed an immature myeloid phenotype, with frequent expression of CD34 (33/35; 94%), CD117 (31/35; 89%), HLA-DR (34/34; 100%), and uniform CD123 positivity in all evaluable cases (22/22; 100%), along with FLT3-ITD and WT1 alterations (22/34 each; 65%) and mostly diploid karyotypes (61%). NUP98::KDM5A occurred in younger children (median age at diagnosis, 1.9 years) and was associated with erythroid/megakaryocytic differentiation, including CD41/CD61 positivity in 8 of 10 (80%) and glycophorin A positivity in 3 of 9 (33%) evaluable cases. Chromosome 13 abnormalities and RB1 alterations were identified in 60% and 55% of evaluable cases, respectively, and complex karyotypes were present in 63% of cases. Other NUP98 fusions (NUP98::X; n = 15, 24%) showed diverse phenotypes and were enriched for 11p abnormalities (79% of evaluable NUP98::X cases). Most 11p abnormalities were evident on conventional cytogenetics when karyotype data were available, in contrast to NUP98::NSD1 and NUP98::KDM5A cases, which were often cytogenetically cryptic. In summary, the NUP98 fusion partner was associated with recurring, diagnostically useful immunophenotypic, cytogenetic, and molecular patterns. These patterns can facilitate prioritization of RNA-based fusion testing, anticipate partner-specific differentials, and design flow cytometry follow-up strategies.
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