Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

Nat Med. 2013 Mar;19(3):368-71. doi: 10.1038/nm.3078. Epub 2013 Feb 3.


Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.

MeSH terms

  • 5'-Nucleotidase / genetics*
  • 5'-Nucleotidase / metabolism
  • Antineoplastic Agents / therapeutic use*
  • Arabinonucleosides / pharmacology
  • Arabinonucleosides / therapeutic use
  • Base Sequence
  • Cell Line
  • Drug Resistance, Neoplasm / genetics*
  • HEK293 Cells
  • Humans
  • Mercaptopurine / therapeutic use*
  • Mutation
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Recurrence
  • Sequence Analysis, DNA
  • Thioguanine / therapeutic use


  • Antineoplastic Agents
  • Arabinonucleosides
  • nelarabine
  • Mercaptopurine
  • 5'-Nucleotidase
  • NT5C2 protein, human
  • Thioguanine