NUTD5 forms the fulcrum of thiopurine toxicity and resistance

Thiopurines are a class of drugs that suppress the immune system. They are used to treat cancers, such as pediatric acute lymphoblastic leukemia, and certain autoimmune disorders, including inflammatory bowel diseases. While effective therapeutics, their use is currently restricted as they can suppress healthy blood cell formation (myelosuppression). A study led by Jun J. Yang, PhD, St. Jude Department of Pharmacy & Pharmaceutical Sciences, found the protein NUTD5 acts as a fulcrum to regulate purine metabolism and hence thiopurine responses. NUTD5 hyperactivation led to greater toxicity, but NUTD5 loss led to thiopurine treatment resistance. The findings, which may enable the development of individualized thiopurine therapies, were published in The Journal of Clinical Investigation. 

“Even though we began this project with a narrow goal to look for genes driving thiopurine drug resistance, the work quickly evolved to reveal novel principles of how cells regulate nucleotide metabolism,” Yang said. “Once again, studying drug metabolism has led us to fundamental insights into cancer cell biology.”

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