Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia

Nature. 2018 Jan 25;553(7689):511-514. doi: 10.1038/nature25186. Epub 2018 Jan 17.


Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.

Publication types

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

MeSH terms

  • 5'-Nucleotidase / genetics*
  • 5'-Nucleotidase / metabolism*
  • Animals
  • Cell Proliferation
  • Clonal Evolution*
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gain of Function Mutation / genetics
  • Guanosine / biosynthesis
  • HEK293 Cells
  • Humans
  • IMP Dehydrogenase / antagonists & inhibitors
  • IMP Dehydrogenase / metabolism
  • Male
  • Mercaptopurine / pharmacology
  • Mercaptopurine / therapeutic use
  • Mice
  • Mutation / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Purines / metabolism
  • Receptor, Notch1 / metabolism
  • Recurrence
  • Xenograft Model Antitumor Assays


  • Notch1 protein, mouse
  • Purines
  • Receptor, Notch1
  • Guanosine
  • Mercaptopurine
  • IMP Dehydrogenase
  • 5'-Nucleotidase
  • NT5C2 protein, human
  • purine