New Investigator Research Grant Program

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that often returns after treatment, with very limited options for targeted therapy. T-ALL comes from early T cells in the body, which normally rely on specific signals to grow and survive. We discovered that blocking a key signal in these leukemia cells—called pre-TCR signaling—can make the cells die, especially when combined with drugs that activate the cell’s natural “self-destruct” program. In our search for important proteins that support these cancer-driving signals, we found a protein called SASH3 that plays a key role. SASH3 helps healthy and cancerous T cells stay alive and grow. Rare mutations in this gene cause immune deficiencies in humans, but it has not been studied in T-ALL. We found that SASH3 and its modified forms (phosphorylated versions) are highly active in patient leukemia samples. Removing SASH3 from leukemia cells reduced their ability to survive and spread in our laboratory models of T-ALL. To further understand the role of SASH3, we created a new mouse model that lacks this protein in blood-forming cells. These mice showed weaker immune development and more T cell death, suggesting SASH3 is critical for T cell survival. Our goal is to understand how SASH3 helps T-ALL grow, and whether blocking it could be a new way to treat the disease. This research could open the door to developing a new, more effective therapy for patients with this deadly leukemia.