The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53.
Direct targeting of NT5C2 or inhibition of compensatory pathways active in <i>NT5C2</i> mutant cells may antagonize the emergence of <i>NT5C2</i> mutant clones driving resistance and relapse in ALL.
Here, we present kinetic and structural properties of cN-II variants that represent 75 % of mutated alleles in patients who experience relapsed ALL (R367Q, R238W and L375F).
These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.