Tandem Duplications in UBTF Create XPO1-Dependent Nuclear Export Signals that Reveal a Leukemic Therapeutic Dependency

UBTF tandem duplications (UBTF-TD) define a high-risk molecular subtype of acute myeloid leukemia (AML). Although menin inhibitors show therapeutic promise in UBTF-TD AMLs, acquired resistance remains a challenge. In this study, we used proteomic, epigenetic, and functional analyses to uncover mechanisms underlying UBTF-TD leukemogenesis. Biochemical studies showed that UBTF-TDs result in structural destabilization and create nuclear export signal (NES) motifs, which mediate direct interactions with exportin-1 (XPO1). In cord blood CD34+ UBTF-TD models, these interactions were shown to drive aberrant chromatin binding and transcriptional activation of genes dysregulated in UBTF-TD tumors. Through mutagenesis, we demonstrated that these NES motifs are critical for localization of UBTF-TD proteins to chromatin, transcriptional dysregulation, and cellular proliferation and differentiation. In preclinical UBTF-TD models of human leukemia, we found that XPO1 inhibition disrupts UBTF-TD chromatin localization, reduces tumor burden, and promotes differentiation. These mechanistic findings highlight XPO1 inhibition as a potential therapy for UBTF-TD AMLs. Significance: UBTF tandem duplications are a high-risk AML subtype. We identified a mechanism in which UBTF-TDs result in the generation of NES motifs, enabling aberrant interaction with XPO1. We found that XPO1 inhibitors block this interaction and impair leukemia growth, identifying a possible therapeutic strategy in UBTF-TD AML. See related commentary by Adams, p. 15.