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Clonal evolution mechanisms in NT5C2 mutant/relapsed acute lymphoblastic leukaemia

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dc.contributor.authorTzoneva, G.
dc.contributor.authorDieck, C.L.
dc.contributor.authorOshima, K.
dc.contributor.authorAmbesi-Impiombato, A.
dc.contributor.authorSanchez-Martin, M.
dc.contributor.authorMadubata, C.J.
dc.contributor.authorKhiabanian, H.
dc.contributor.authorYu, J.
dc.contributor.authorWaanders, E.
dc.contributor.authorIacobucci, I.
dc.contributor.authorSulis, M.L.
dc.contributor.authorKato, M.
dc.contributor.authorKoh, K.
dc.contributor.authorPaganin, M.
dc.contributor.authorBasso, G.
dc.contributor.authorGastier-Foster, J.M.
dc.contributor.authorLoh, M.L.
dc.contributor.authorKirschner-Schwabe, R.
dc.contributor.authorMullighan, C.G.
dc.contributor.authorAbadan, R.R.
dc.contributor.authoret al.
dc.date.issued2018
dc.description.abstractRelapsed 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.
dc.description.statementofresponsibilityGannie Tzoneva, Chelsea L. Dieck, Koichi Oshima, Alberto Ambesi-Impiombato, Marta Sánchez-Martín ... Charles G. Mullighan ... et al.
dc.identifier.citationNature, 2018; 553(7689):511-+
dc.identifier.doi10.1038/nature25186
dc.identifier.issn0028-0836
dc.identifier.issn1476-4687
dc.identifier.orcidMullighan, C.G. [0000-0002-1871-1850]
dc.identifier.urihttp://hdl.handle.net/2440/117040
dc.language.isoen
dc.publisherNature Research
dc.rights© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
dc.source.urihttps://doi.org/10.1038/nature25186
dc.subjectDrug Resistance, Neoplasm
dc.titleClonal evolution mechanisms in NT5C2 mutant/relapsed acute lymphoblastic leukaemia
dc.typeJournal article
pubs.publication-statusPublished

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