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https://hdl.handle.net/2440/117040
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Type: | Journal article |
Title: | Clonal evolution mechanisms in NT5C2 mutant/relapsed acute lymphoblastic leukaemia |
Author: | Tzoneva, G. Dieck, C.L. Oshima, K. Ambesi-Impiombato, A. Sanchez-Martin, M. Madubata, C.J. Khiabanian, H. Yu, J. Waanders, E. Iacobucci, I. Sulis, M.L. Kato, M. Koh, K. Paganin, M. Basso, G. Gastier-Foster, J.M. Loh, M.L. Kirschner-Schwabe, R. Mullighan, C.G. Abadan, R.R. et al. |
Citation: | Nature, 2018; 553(7689):511-+ |
Publisher: | Nature Research |
Issue Date: | 2018 |
ISSN: | 0028-0836 1476-4687 |
Statement of Responsibility: | Gannie Tzoneva, Chelsea L. Dieck, Koichi Oshima, Alberto Ambesi-Impiombato, Marta Sánchez-Martín ... Charles G. Mullighan ... et al. |
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. |
Keywords: | Drug Resistance, Neoplasm |
Rights: | © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. |
DOI: | 10.1038/nature25186 |
Published version: | http://dx.doi.org/10.1038/nature25186 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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