Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia.
Nature
; 553(7689): 511-514, 2018 01 25.
Article
em En
| MEDLINE
| ID: mdl-29342136
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
5'-Nucleotidase
/
Resistencia a Medicamentos Antineoplásicos
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Leucemia-Linfoma Linfoblástico de Células Precursoras
/
Evolução Clonal
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Mutação
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Nature
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos