ZEBRAFISH XENOTRANSPLANTATION AS A PRECLINICAL THERAPEUTIC PLATFORM FOR T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Abstract

Pediatric T-cell Acute Lymphoblastic leukemia (T-ALL) is a high-risk disease. There is a need for targeted therapies for T-ALL, and techniques to rapidly screen drug candidates and personalize patient therapy. I developed a zebrafish xenotransplantation (XT) model to screen novel agents for efficacy and toxicity. I demonstrated that T-ALL cell lines recapitulate in vitro responses to targeted therapies in vivo. Importantly, patient-derived lymphoblasts engraft in zebrafish and specific drug responses can be quantitatively determined. I identified a mutation sensitive to γ-secretase inhibition in a xenograft from a child with T-cell acute lymphoblastic leukemia, confirmed by Sanger sequencing and validated as a gain-of-function NOTCH1 mutation. Furthermore, I employed the zebrafish XT assay to determine the efficacy of two novel compounds to protect against doxorubicin-induced cardiac damage. The zebrafish XT platform provides a novel cost-effective means of screening novel agents, and tailoring leukemia therapy in real-time to maximize efficacy and minimize toxicity.