Abstract A019 Genetic and epigenetic characterization of NUP98-rearranged leukemia

Abstract Introduction Pediatric acute myeloid leukemia (AML) with NUP98 rearrangements (NUP98r) is associated with dismal prognoses. NUP98 fusion partners are linked with specific AML subtypes, such as NUP98::NSD1 with myeloblastic AML and NUP98::KDM5A with acute megakaryocytic leukemia (AMKL). Although mostly present in AML, various NUP98r are also found in other malignancies such as T-cell acute lymphoblastic leukemia (T-ALL) and myelodysplastic syndrome (MDS). Despite genomic studies showing associations between FLT3 internal tandem duplications (FLT3-ITD) and WT1 mutations with NUP98::NSD1 AML, the genome-wide mutational status of NUP98r leukemias is to be elucidated. Also, experimental models showed that NUP98 fusion oncoproteins (FOs) regulate gene expression by binding to genomic loci such as HOX genes or MEIS1; however, how different partners contribute to specific diseases remains unstudied. Methods We established a pediatric NUP98r leukemia cohort consisting of 185 samples from 177 cases from our institute, public databases, or collaborators. AML is the dominant disease (n=154), whereas it also included T-ALL (n=18), therapy-related myeloid neoplasms (t-MN, n=4), and MDS (n=1). RNA-sequencing (RNA-seq) data was obtained for all samples, and whole-genome/exome sequencing (WGS/WES) data was obtained from 94 samples. Fusion genes were called from RNA-seq. Somatic alterations were called from both WGS/WES and RNA-seq. The epigenetic status and NUP98 FO-binding of 14 cases were studied using CUT 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A019.