Activating NT5C2 mutations occur in 10% to 16% of patients with relapsed ALL.
Major finding: Activating NT5C2 mutations occur in 10% to 16% of patients with relapsed ALL.
Mechanism: NT5C2 is a 5′-nucleotidase that inactivates purine analogues used in standard ALL therapy.
Impact: Acquired NT5C2 mutations increase nucleoside analogue metabolism and promote drug resistance in ALL.
Although the vast majority of pediatric patients with acute lymphoblastic leukemia (ALL) can be cured with intensive chemotherapy, the prognosis for children with relapsed disease is poor. To identify possible genetic causes of chemoresistance and relapse, Tzoneva and colleagues performed whole-exome sequencing of samples from patients with pediatric T-cell ALL (T-ALL), and Meyer and colleagues performed RNA sequencing of patients with B-cell ALL (B-ALL). Intriguingly, both approaches identified mutations in NT5C2 in relapsed ALL that were absent from diagnosis and remission DNA, and targeted sequencing in independent larger cohorts uncovered NT5C2 mutations in 10% to 16% of patients with relapsed ALL. NT5C2 encodes a ubiquitous cytosolic 5′-nucleotidase (also known as cN-II) that regulates cellular purine nucleotide levels by dephosphorylating 5′-inosine monophosphate and 5′-guanosine monophosphate nucleotides and converting them to inosine and guanosine nucleosides, respectively. Of note, NT5C2 can also dephosphorylate and inactivate thiopurine nucleotides that are the active metabolites of the purine analogues 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) used as part of standard ALL therapy. Multiple patients shared the same NT5C2 mutations, and the vast majority of the observed mutations clustered in the same region of the NT5C2 protein, suggesting that these mutations might lead to a gain of enzymatic function that would promote resistance to nucleoside analogues. Indeed, recombinant NT5C2 mutant proteins had significantly higher enzymatic activity than wild-type NT5C2 in vitro, and expression of NT5C2 mutants in T-ALL and B-ALL cell lines conferred resistance to 6-MP and 6-TG. In addition, both groups found that NT5C2 mutations were associated with a significantly shorter time to relapse and in some cases could be present in a minor subclone at diagnosis. Together, these findings implicate increased nucleoside analogue metabolism caused by activating mutations in NT5C2 in the evolution of disease progression and chemoresistance in ALL.
Tzoneva G, Perez-Garcia A, Carpenter Z, Khiabanian H, Tosello V, Allegretta M, et al. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nat Med 2013 Feb 3 [Epub ahead of print].