Fusion oncoproteins and cooperating mutations define disease phenotypes in <i>NUP98</i>-rearranged leukemia.

ABSTRACT: Leukemias with NUP98 rearrangements exhibit heterogeneous phenotypes correlated to fusion partners, whereas the mechanism responsible for this heterogeneity is poorly understood. Through genome-wide mutational and transcriptional analyses of 177 NUP98-rearranged leukemias, we show that cooperating alterations are associated with differentiation status even among leukemias sharing the same NUP98 fusions, such as NUP98::KDM5A acute megakaryocytic leukemia with RB1 loss or T-cell acute lymphoblastic leukemia with NOTCH1 mutations. CUT&RUN profiling reveals that NUP98 fusion oncoproteins directly regulate differentiation-related genes, with binding patterns also influenced by differentiation stage. Using in vitro models, we show RB1 loss

SUBMITTER: Umeda M 

PROVIDER: S-EPMC11838931 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature