Fusion Oncoproteins and Cooperating Mutations Define Disease Phenotypes in NUP98-Rearranged Leukemia
- PMID: 40700635
- DOI: 10.1182/blood.2025028993
Fusion Oncoproteins and Cooperating Mutations Define Disease Phenotypes in NUP98-Rearranged Leukemia
Abstract
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. In patient samples, NUP98-fusion oncoprotein binding patterns are heterogeneous, potentially shaped by somatic mutations and differentiation status. Using cbCD34 models and CRISPR/Cas9 gene editing, we show that RB1 loss cooperates with NUP98::KDM5A by blocking terminal differentiation toward platelets and expanding megakaryocyte-like cells, whereas WT1 frameshift mutations skew differentiation toward dormant lymphoid-myeloid primed progenitor cells and cycling granulocyte-monocyte progenitor cells, providing evidence for NUP98-rearranged leukemia phenotypes affected by cooperating alterations. NUP98::KDM5A cbCD34 models with RB1 or WT1 alterations have different sensitivities to menin inhibition, suggesting that cellular differentiation provides stage-specific menin dependencies and resistance mechanisms that can be leveraged for future treatment strategies for NUP98-rearranged leukemia.
Copyright © 2025 American Society of Hematology.
Update of
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Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia.medRxiv [Preprint]. 2025 Jan 22:2025.01.21.25320683. doi: 10.1101/2025.01.21.25320683. medRxiv. 2025. Update in: Blood. 2025 Jul 23:blood.2025028993. doi: 10.1182/blood.2025028993. PMID: 39974131 Free PMC article. Updated. Preprint.
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