Scientists at St. Jude Children’s Research Hospital have pinpointed a critical mechanism behind a treatment-resistant form of acute myeloid leukemia (AML) in children, opening the door to a potential new therapeutic strategy.
The findings, focused on a subtype driven by a genetic anomaly known as UBTF tandem duplication (UBTF-TD), were published today in the journal Blood Cancer Discovery. This aggressive pediatric cancer has a high risk of relapse, making the discovery of a viable drug target a significant advancement for the field.
Understanding the Aggressive Foe: UBTF-TD AML
UBTF-TD AML is recognized by oncologists as a particularly challenging subtype of acute myeloid leukemia. It is characterized by its resistance to standard chemotherapy and a frustrating tendency to recur. Prior research from the St.
Jude team had already shown that UBTF-TD plays a role in overdriving cancer-causing genes and identified a potential vulnerability to a class of drugs known as Menin inhibitors. This new study delves deeper into the fundamental mechanics of how the abnormal UBTF-TD protein functions, uncovering a separate and powerful driver of the disease.
A Rogue Signal Exposed by Genetic Flaw
The research team used a combination of genomic, proteomic, and structural biology techniques to understand how UBTF-TD functions differently from the normal protein. Their investigation revealed a surprising finding: the abnormal protein was interacting strongly with Exportin-1, a cellular machine responsible for transporting molecules outof the nucleus.
“We discovered that the tandem repeats in the UBTF gene create an illegitimate signal—a rogue handle—that is grabbed by Exportin-1,” explained co-first author Juan Barajas, Ph.D., of the St. Jude Department of Pathology.
Structural Biology Confirms the Hijacking Mechanism
Through detailed structural analysis, the team confirmed how this hijacking occurs. The repetitive genetic sequence disrupts the normal, folded structure of the UBTF protein. This misfolding exposes an amino acid sequence that mimics a nuclear export signal (NES), which is precisely what Exportin-1 is designed to recognize and bind.
“We tested all the tandem repeats and found they all exposed this same sequence,” said co-first author Aaron Phillips, Ph.D., of the St. Jude Department of Structural Biology. “This isn’t the protein’s normal function; it’s a direct and unintended consequence of the genetic duplication.”
Driving Cancer by Misguided Localization
The critical twist is what happens next. Instead of Exportin-1 carrying the UBTF-TD protein out of the nucleus as it normally would, the complex is rerouted to specific genes known to be dysregulated in AML.
Once positioned there, UBTF-TD acts as a powerful activator, fueling abnormal gene expression that drives the uncontrolled cell growth characteristic of leukemia. This misguided localization is central to the cancer’s development.
A Promising Path to a New Treatment
The most immediate impact of this discovery is the identification of a promising therapeutic target. When the researchers used an Exportin-1 inhibitor in patient-derived models, it successfully disrupted the harmful UBTF-TD/Exportin-1 interaction.
This intervention reduced the mislocalization of the protein and, most importantly, slowed tumor growth. This provides a strong scientific rationale for exploring existing Exportin-1 inhibitors, some of which are already in clinical development for other cancers, as a potential new treatment for children with UBTF-TD AML.
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