Genetics and mechanisms of NT5C2-driven chemotherapy resistance in relapsed ALL

Mutations in the cytosolic 59 nucleotidase II (NT5C2) gene drive resistance to thiopurine chemotherapy in relapsed acute lymphoblastic leukemia (ALL). Mechanistically, NT5C2 mutant proteins have increased nucleotidase activity as a result of altered activating and autoregulatory switch-off mechanisms. Leukemia cells harboring activating NT5C2 mutations are chemo-resistant to 6-mercaptopurine (6-MP), yet show impaired proliferative and self-renewal capacity. Direct inhibition of NT5C2 or pharmacologic targeting of compensatory pathways active in NT5C2 mutant cells may antagonize the emergence of NT5C2 mutant clones driving resistance and relapse in ALL.