Fusion Oncoproteins and Cooperating Mutations Define Disease Phenotypes in NUP98-Rearranged Leukemia.

Leukemias with NUP98 rearrangements exhibit heterogeneous phenotypes such as acute myeloid leukemia (AML), T-acute lymphoblastic leukemia (T-ALL), or myelodysplastic syndrome/neoplasms (MDS) associated with 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 (AMKL) with RB1 loss or T-ALL with NOTCH1 mutations. CUT&RUN profiling of in vitro cord blood CD34+ cell (cbCD34) models of major NUP98 fusions revealed that NUP98 fusion oncoproteins directly regulate differentiation-related genes contributing to the disease phenotypes, represented by NUP98::KDM5A binding to MEIS2 or GFI1B for megakaryocyte differentiation.