Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia.

Abstract

Relapsed acute lymphoblastic leukemia (ALL) is associated with chemotherapy resistance and poor prognosis1. Gain-of-function mutations in the 5′-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine (6-MP) and are selectively present in relapsed ALL2,3. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during leukemia initiation, disease progression and relapse remain unknown. Using a conditional inducible leukemia model, we demonstrate that expression of Nt5c2 p.R367Q, a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-MP at the cost of impaired leukemia cell growth and leukemia-initiating cell activity. The loss of fitness phenotype of Nt5c2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine nucleotide pool. Consequently, blocking guanosine synthesis via inosine-5′-monophosphate dehydrogenase (IMPDH) inhibition induced increased cytotoxicity against NT5C2-mutant leukemia lymphoblasts. These results identify NT5C2 mutation-associated fitness cost and resistance to chemotherapy as key evolutionary drivers shaping clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.