Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL Academic Article uri icon

Overview

MeSH Major

  • 5'-Nucleotidase
  • 6-Mercaptopurine
  • Antineoplastic Agents
  • Drug Resistance, Neoplasm
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma

abstract

  • 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.

publication date

  • March 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3594483

Digital Object Identifier (DOI)

  • 10.1038/nm.3078

PubMed ID

  • 23377281

Additional Document Info

start page

  • 368

end page

  • 71

volume

  • 19

number

  • 3