Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-01

AUTHORS

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

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. More... »

PAGES

511

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature25186

    DOI

    http://dx.doi.org/10.1038/nature25186

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1100458150

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29342136


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