Targeting KAT2A-Dependent Oncogenic Transcriptional Programs in Pediatric AML Using a Novel Molecular Glue Degrader
Pediatric acute myeloid leukemia (AML) is a type of blood cancer affecting children and adolescents. Despite advances in therapy, survival has improved only modestly over the past decades, and relapse or treatment-resistant disease remains deadly. In AML, genetic changes can hijack the cell’s normal control systems, making key “switchboard operators” - proteins called transcription factors that coordinate multiple cellular programs - drive cells toward cancerous growth. Targeting these switchboard operators directly has proven extremely difficult. One protein, KAT2A, acts as an “amplifier,” boosting the signals from transcription factors and helping leukemia cells survive and multiply. Until now, there were no therapies that could selectively target KAT2A. A team at Dana-Farber Cancer Institute has now developed WM-03-166, a first-of-its-kind drug (called a molecular glue degrader) which can specifically destroy KAT2A. My studies show that removing KAT2A with WM-03-166 halts leukemia growth, triggers cancer cells to mature into normal blood cells, and improves survival in animal models of AML. I have also found that KAT2A works closely with one famous switchboard operator, MYC, helping it drive leukemia programs, suggesting that targeting KAT2A may be a way to indirectly suppress even the most challenging cancer drivers.
Project Goals
This project focuses on a high-risk subtype of pediatric AML called KMT2A-driven AML, which is particularly aggressive and difficult to treat. We aim to understand how KAT2A amplifies leukemia-driving programs in KMT2A-driven AML, including its collaboration with MYC, and to test whether removing it with WM-03-166 can be a novel, effective treatment for kids with AML. First, we will identify the genes and DNA regions controlled by KAT2A to reveal the cancer-promoting programs it helps maintain. Next, we will study how KAT2A directly works with MYC to sustain leukemia cell survival. Finally, we will test WM-03-166 in lab grown and patient-derived KMT2A-driven leukemia models, measuring its ability to halt cancer growth, promote cancer cells to mature into normal blood cells, and improve survival. The ultimate goal is to provide the evidence needed to bring WM-03-166 into clinical trials for kids with this aggressive type of AML. Success could offer a lifesaving treatment for high-risk pediatric AML and establish a framework for translating similar approaches to other childhood cancers driven by similar cancer gene programs. In addition, this work would identify markers to predict which children are most likely to benefit, laying the groundwork for safer, more precise treatments.
