Mentor Name: Jessica Blackburn

Relapsed T-cell acute lymphoblastic leukemia (T-ALL) remains a major cause of treatment failure in pediatric patients and is driven in part by a rare population of leukemia-initiating cells (LICs) that are resistant to chemotherapy. These cells rely on specialized metabolic and survival programs that are not well targeted by current therapies. This project focuses on the sodium–hydrogen exchanger NHE1, a key regulator of intracellular pH and ion homeostasis that has been implicated in cancer cell fitness and stress tolerance. Our prior work has identified NHE1 as an important regulator of leukemia-initiating cell fitness and self-renewal in T-ALL, providing a strong rationale for testing whether NHE1 disruption alters chemotherapy response. Using both in vitro cell culture systems and in vivo zebrafish leukemia models, this project will test how genetic knockdown or pharmacologic inhibition of NHE1 affects LIC survival and sensitivity to standard chemotherapies. By examining treatment response in complementary experimental systems, this work aims to determine whether disrupting ion homeostasis can weaken therapy-resistant leukemia cells and improve treatment efficacy. These studies will provide insight into fundamental mechanisms of chemotherapy resistance and may inform new strategies for targeting high-risk pediatric T-ALL.