Mechanisms and Therapeutic Targets of UBTF Tandem Duplication in Pediatric Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is an aggressive cancer of the blood and bone marrow. It starts in stem cells that should normally become healthy white or red blood cells, but instead turn into leukemia cells that grow uncontrollably. AML can affect people of all ages, but some of the most dangerous forms occur in children and teenagers. These patients often require intense chemotherapy, hospitalization, and sometimes bone marrow transplants. Even with these treatments, some children relapse, and options become limited. Recently, researchers discovered a new subtype of AML caused by a change in a gene called UBTF. In some children or young adults with AML, UBTF acquires an abnormal repeated segment called a “tandem duplication” (UBTF-TD). This change alters how blood cells function and is linked to treatment resistance and poor outcomes. Besides, UBTF-TD often appears with other mutations, such as WT1 or FLT3, which may make the disease even more aggressive. Given the clinical significance, there are no targeted therapies that exist, and families face an urgent need for better treatment strategies.
Project Goals
Our project aims to understand how UBTF-TD causes leukemia in young patients and to identify better treatment options. First, we will study leukemia samples from children using advanced single-cell technologies. These methods allow us to analyze thousands of individual cancer cells at once—revealing patterns that are invisible with traditional approaches. We hope to learn what makes UBTF-TD leukemia behave differently from other forms of AML. We also created a laboratory model of UBTF-TD AML using human blood stem cells and CRISPR gene editing. These engineered cells behave like leukemia cells, showing that the UBTF-TD mutation can drive disease. When we added a second mutation commonly seen in patients (WT1), the cells changed the gene expression profile and behaviors, suggesting that these mutations work together to worsen leukemia. By transplanting these engineered cells to mice, we developed the animal model needed to better characterize how these mutations change cell behavior and to test potential therapeutic strategies. Using these models, we will test therapies that may work specifically against UBTF-TD cells, including drugs called Menin inhibitors, which are already being explored for other leukemias. Our goal is to provide a foundation for safer, more effective treatments for children and adolescents facing this high-risk subtype.
