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

At the heart of this research lies a specific protein isoform, RUNX1C, which is a variant product of the RUNX1 gene, known to be a critical regulator of normal blood cell differentiation and function. This isoform had been relatively understudied, but the JAX team, led by assistant professor Eric Wang, has uncovered its pivotal role in enabling AML cells to withstand chemotherapy and enter a protective dormant state. The study, published in the prestigious journal Blood Cancer Discovery, underscores a sophisticated regulatory axis involving RUNX1C and a downstream gene, BTG2, which together orchestrate the quiescence and survival of leukemia cells in the face of genotoxic stress from chemotherapeutic agents.

The investigation employed a comprehensive analysis of patient-derived data, examining samples taken before chemotherapy and after AML relapse. Remarkably, the researchers identified a pronounced increase in DNA methylation—a chemical modification that generally suppresses gene expression—in a genomic region controlling RUNX1. This epigenetic switch led to enhanced production of the RUNX1C isoform specifically, rather than a general increase in RUNX1 expression. This precision epigenetic alteration is critical because it activates a cascade of molecular events that skew the leukemia cells toward chemoresistance.

Delving deeper into mechanism, it was revealed that RUNX1C upregulates the BTG2 gene. BTG2 functions as a cell cycle regulator by interfering with RNA activity, effectively dampening cellular proliferation signals. The consequence is a shift in leukemia cells to enter a quiescent or dormant state, wherein they cease dividing and thus evade the cytotoxic effects of chemotherapy, which preferentially targets rapidly dividing cells. This cellular dormancy effectively cloaks the cancer cells from therapeutic elimination, allowing them to persist silently and ultimately rekindle disease when treatment ceases.

Wang emphasizes the clinical implications of these findings, noting the scarcity of effective treatments for AML patients who relapse following standard chemotherapy regimens. This research not only elucidates the molecular underpinnings of relapse but also identifies RUNX1C as a strategically viable target for therapeutic intervention. Importantly, the team demonstrated that experimentally inhibiting RUNX1C in AML cellular models and mouse systems significantly lowered chemoresistance, as cancer cells were forced out of quiescence, becoming once again vulnerable to chemotherapeutic drugs.

Central to this innovative approach is the application of antisense oligonucleotides (ASOs), sophisticated RNA-targeting molecules capable of binding to specific RNA transcripts and blocking protein production. While ASO technology has seen success in rare neurological disorders, its use in AML and other cancers remains largely unexplored. The promising results from Wang’s lab suggest that ASOs engineered specifically to suppress RUNX1C expression could restore chemotherapy sensitivity by preventing leukemia cells from entering dormancy, offering a potent combination strategy alongside conventional treatments.

The functional experiments conducted by Dr. Cuijuan Han, the study’s lead author, further validated the causative role of RUNX1C in chemoresistance. Overexpression of RUNX1C rendered AML cells resistant to multiple chemotherapeutic drugs, while genetic silencing of this isoform sensitized cells, underscoring a direct link between RUNX1C abundance and therapy outcomes. These meticulously executed gain- and loss-of-function studies highlight the isoform-specific nature of chemoresistance mechanisms, an aspect previously overlooked in AML research.

This work also serves as an important proof of concept that RNA isoforms—which arise from alternative processing of the same gene transcript—are not mere biological noise but critical regulators of cancer cell behavior. Such isoform-specific targeting may revolutionize the understanding and treatment of not only AML but potentially a broad spectrum of cancers. Wang notes the potential to extend these insights, proposing future research to explore isoform modulation across different malignancies and therapeutic contexts.

Beyond its immediate translational potential, this research adds a novel layer to the complex understanding of cancer biology. The epigenetic regulation of gene isoforms introduces a nuanced dimension to how leukemic cells adapt to and resist chemotherapeutic pressure. It shifts the paradigm from focusing solely on gene-level expression changes to appreciating the diversity of RNA isoforms driving disease progression. This enhanced comprehension could inform biomarker development and therapeutic design, optimizing individualized treatment strategies.

The Jackson Laboratory team plans to continue refining RNA-targeting technologies to enhance specificity and efficacy in vivo, as well as to investigate combinational therapies pairing ASOs with emerging targeted agents. They envision that the tailored inhibition of RUNX1C could be integrated into multi-modal treatment regimens, improving remission durability and ultimately patient survival. Given the high relapse rate and dismal prognosis for relapsed AML patients, such advancements could markedly shift clinical outcomes.

In conclusion, the JAX study illuminates a transformative avenue in cancer therapeutics by pinpointing an isoform-specific pathway that governs leukemia cell dormancy and chemoresistance. Through the innovative use of RNA-targeting antisense technology, there is newfound hope for overcoming one of the most stubborn hurdles in AML treatment. This research not only enhances fundamental cancer biology knowledge but also foreshadows the arrival of precision molecular interventions capable of disabling the stealth tactics employed by lethal cancers.

Subject of Research: Animals

Article Title: An Isoform-Specific RUNX1C–BTG2 Axis Governs AML Quiescence and Chemoresistance

News Publication Date: 11-Aug-2025

Web References:

• https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-24-0327/764069/An-Isoform-Specific-RUNX1C-BTG2-Axis-Governs-AML
• http://dx.doi.org/10.1158/2643-3230.BCD-24-0327

References:
Wang, E., Han, C., et al. An Isoform-Specific RUNX1C–BTG2 Axis Governs AML Quiescence and Chemoresistance. Blood Cancer Discovery. 11 August 2025.

Image Credits: The Jackson Laboratory

Keywords: Leukemia, Myeloid leukemia, RNA