Tandem duplications in UBTF create XPO1-dependent nuclear export signals necessary for leukemic progression [CUT&Run]

UBTF tandem duplications (UBTF-TD) define a high-risk molecular subtype of acute myeloid leukemia (AML) characterized by poor clinical outcomes. While menin inhibitors have shown therapeutic promise, acquired resistance remains a significant challenge. Here, we use proteomic, genomic, and functional analyses to uncover mechanisms underlying UBTF-TD mediated leukemogenesis. We show that TDs create nuclear export signal (NES) motifs, which mediate interactions with Exportin-1 (XPO1) and chromatin-associated partners. These interactions drive aberrant chromatin binding and transcriptional activation of genes commonly dysregulated in UBTF-TD tumors, including the HOXA/HOXB clusters. We demonstrate that these NES motifs are critical for mislocalization of UBTF-TD proteins, cellular transformation, and transcriptional dysregulation. Importantly, we identify the XPO1 inhibitor eltanexor as a potential therapeutic strategy. Eltanexor treatment disrupts UBTF-TD chromatin localization, reduces tumor burden, and promotes differentiation in preclinical models. These findings provide mechanistic insights into UBTF-TD-driven leukemogenesis and highlight XPO1 inhibition as a promising therapy for UBTF-TD AMLs.