Genetics and mechanisms of NT5C2-driven chemotherapy resistance in relapsed ALL

Blood. 2019 May 23;133(21):2263-2268. doi: 10.1182/blood-2019-01-852392. Epub 2019 Mar 25.


Mutations in the cytosolic 5' nucleotidase II (NT5C2) gene drive resistance to thiopurine chemotherapy in relapsed acute lymphoblastic leukemia (ALL). Mechanistically, NT5C2 mutant proteins have increased nucleotidase activity as a result of altered activating and autoregulatory switch-off mechanisms. Leukemias with NT5C2 mutations are chemoresistant to 6-mercaptopurine yet show impaired proliferation and self-renewal. Direct targeting of NT5C2 or inhibition of compensatory pathways active in NT5C2 mutant cells may antagonize the emergence of NT5C2 mutant clones driving resistance and relapse in ALL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 5'-Nucleotidase*
  • Cell Proliferation* / drug effects
  • Cell Proliferation* / genetics
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Humans
  • Mercaptopurine / therapeutic use*
  • Mutation*
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / enzymology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / pathology


  • Neoplasm Proteins
  • Mercaptopurine
  • 5'-Nucleotidase
  • NT5C2 protein, human