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Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia.

  • Author(s): Tzoneva, Gannie
  • Dieck, Chelsea L
  • Oshima, Koichi
  • Ambesi-Impiombato, Alberto
  • Sánchez-Martín, Marta
  • Madubata, Chioma J
  • Khiabanian, Hossein
  • Yu, Jiangyan
  • Waanders, Esme
  • Iacobucci, Ilaria
  • Sulis, Maria Luisa
  • Kato, Motohiro
  • Koh, Katsuyoshi
  • Paganin, Maddalena
  • Basso, Giuseppe
  • Gastier-Foster, Julie M
  • Loh, Mignon L
  • Kirschner-Schwabe, Renate
  • Mullighan, Charles G
  • Rabadan, Raul
  • Ferrando, Adolfo A
  • et al.

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.

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