Acute myeloid leukemia (AML) remains one of the most challenging pediatric cancers, with certain subtypes demonstrating particularly aggressive behavior and resistance to conventional treatments. One such subtype, driven by tandem duplications within the upstream binding transcription factor gene (UBTF-TD AML), presents a formidable clinical problem, characterized by high relapse rates and treatment refractory disease. Recent groundbreaking research from St. Jude Children’s Research Hospital has uncovered a vital mechanistic insight into this aggressive disease and, importantly, identified a new therapeutic vulnerability that could alter the treatment landscape for affected children worldwide.
The team, led collaboratively by scientists from St. Jude’s Department of Pathology and Department of Structural Biology, focused on the fundamental biological alterations caused by UBTF tandem duplications. Their inquiry revealed that these duplications instill an aberrant nuclear export signal within the UBTF protein. To unravel this, a comprehensive approach combining genomic, proteomic, structural, and functional analyses was employed. This multidisciplinary investigation demonstrated that UBTF-TD does not behave like its normal counterpart but instead gains an unusual interaction with Exportin-1 (XPO1), a key nuclear transport protein traditionally responsible for shuttling molecules out of the nucleus.
Historically, Exportin-1 functions by recognizing and binding nuclear export signals, facilitating the movement of proteins and RNA from the nucleus to the cytoplasm. However, in the case of UBTF-TD, the duplicated segment creates a “rogue” nuclear export signal that hijacks Exportin-1’s trafficking machinery in an unexpected way. Instead of exporting UBTF-TD out of the nucleus, Exportin-1 is co-opted to position the mutated UBTF protein directly at specific genetic loci. These loci correspond to genes whose dysregulation drives leukemogenesis, underpinning the aggressive clinical nature of UBTF-TD AML.
By uncovering this novel protein-protein interaction, the research sheds light on a previously unknown oncogenic mechanism: rather than merely functioning as a passive transcription factor, UBTF-TD exploits nuclear export machinery to remodel gene expression landscapes in favor of leukemic progression. This insight reframes UBTF-TD AML as a disease where aberrant nuclear transport signals are paramount to the cancer’s molecular pathology, providing a fresh angle for therapeutic intervention.
Notably, the team demonstrated that this abnormal association between UBTF-TD and Exportin-1 could be effectively disrupted with selective Exportin-1 inhibitors. These small molecules, already under investigation for other malignancies exhibiting reliance on export pathways, showed promising preclinical efficacy in patient-derived models of UBTF-TD AML. Treatment with Exportin-1 inhibitors significantly reduced tumor burden, confirming the therapeutic potential of targeting this interaction in clinical contexts.
The implications of these findings transcend just UBTF-TD AML. Since nuclear export dysregulation is a feature in various cancers, this work exemplifies how intricate structural biology insights can reveal novel oncogenic mechanisms and corresponding druggable dependencies. Moreover, the collaboration between structural biologists and translational cancer researchers underscores the importance of an integrated scientific approach in tackling complex cancers.
From a mechanistic perspective, the study elucidated that the tandem duplications within UBTF engendered an exposed nuclear export signal due to disruption of a normally folded protein region. Advanced structural analyses employing purified protein complexes confirmed that these duplications destabilize a specific UBTF domain, unveiling an otherwise hidden amino acid sequence that serves as a high-affinity binding site for Exportin-1. This precise structural revelation provided the molecular rationale for the aberrant nuclear transport behavior observed in UBTF-TD AML.
Furthermore, the research team pinpointed the heterogeneous nature of these tandem duplications, noting that while the exact sequence variability exists among patients, they converge functionally by creating similar nuclear export motifs. This explains why multiple distinct tandem duplication events can lead to an identical pathogenic phenotype, an insight crucial for understanding disease heterogeneity and guiding therapeutic development.
The researchers also highlighted the interplay of UBTF-TD with genes that become aberrantly activated, illustrating how this mechanism amplifies oncogene expression driving leukemogenesis. By co-opting Exportin-1 to localize to these pathogenic loci, UBTF-TD enforces a transcriptional program favorable to leukemia maintenance and progression. Interrupting this cycle with Exportin-1 inhibition potentially offers a means to reverse malignant gene expression profiles.
Beyond therapeutic applications, this discovery opens avenues for deeper inquiry into nuclear export dynamics in cancer biology. Understanding how altered nuclear export signals modulate chromatin architecture and gene regulatory networks could reveal further vulnerabilities. Continued dissection of the UBTF-TD/Exportin-1 complex, including other associated biomolecules, promises to uncover even more specific therapeutic targets with improved efficacy and selectivity.
St. Jude’s pioneering investigations into UBTF-TD AML exemplify the rapid translation of molecular insights into actionable clinical strategies. Previously, the lab’s work illuminated Menin inhibitors as a therapeutic option targeting UBTF-TD driven oncogene overexpression. This current study, by identifying a second independent mechanism-centered target, showcases the potential of multi-pronged approaches tailored to the unique molecular signatures of pediatric leukemias.
This research also underscores the critical nature of studying high-risk pediatric cancer subtypes with rigorous experimental methodologies spanning genomics, structural biology, and preclinical modeling. The success of these studies relies heavily on collaborative networks within research institutions that pool expertise to accelerate translational discoveries, exemplified by the partnership between Clincial and Structural Biology labs at St. Jude.
With acute myeloid leukemia in children remaining a deadly disease for many, the revelation of the UBTF-TD and Exportin-1 interaction as a therapeutic dependency marks a hopeful step forward. The development of drugs targeting this axis could, in time, improve outcomes for patients facing this devastating diagnosis. Ultimately, this work invigorates the broader cancer research field to consider nuclear export pathways as critical nodes in oncogenic networks ripe for targeted intervention.
The broader impact of this study will likely prompt renewed focus on the structural determinants of nuclear transport signals altered in cancer, sparking novel avenues for drug discovery. As Exportin-1 inhibitors advance in clinical development, their potential repurposing for treating aggressive leukemias such as UBTF-TD AML could transform pediatric oncology paradigms. Thus, St. Jude’s research not only enriches our molecular understanding but also kindles optimism for targeted therapies that change lives.
Subject of Research: Cells
Article Title: Tandem duplications in UBTF create XPO1-dependent nuclear export signals that reveal a leukemic therapeutic dependency
News Publication Date: 3-Nov-2025
Image Credits: Courtesy of St. Jude Children’s Research Hospital
Keywords: Leukemia
