Juan M. Barajas, Aaron H. Phillips, Jina Wang, Melvin E. Thomas, Lisett Contreras, Masayuki Umeda, Ryan Hiltenbrand, Elizabeth Caldwell, Michael P. Walsh, Guangchun Song, Lauren Ezzell, Kelly Churion, Tamara Westover, Emily Xiong, Chandra Rolle, Jamila Moore, Josi Lott, Sandi Radko-Juettner, Amit Kumar, Wenjie Qi, Beisi Xu, Evangelia K. Papachristou, Clive S. D’Santos, Jing Ma, Burgess B. Freeman, Laura J. Janke, Richard W. Kriwacki, Jeffery M. Klco
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.