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Nature. 2018 Jan 25;553(7689):511-514. doi: 10.1038/nature25186. Epub 2018 Jan 17.

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

Author information

1
Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.
2
Department of Systems Biology, Columbia University, New York, New York 10032, USA.
3
Rutgers Cancer Institute, Rutgers University, New Brunswick, New Jersey 08903, USA.
4
Princess Maxima Center for Pediatric Oncology, Utrecht, 3584 CT, the Netherlands.
5
Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, 6525 GA, the Netherlands.
6
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
7
Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
8
Department of Hematology-Oncology, Saitama Children's Medical Center, Saitama 339-8551, Japan.
9
Onco-Hematology Division, Department, Salute della Donna e del Bambino (SDB), University of Padua, 35128 Padua, Italy.
10
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
11
Department of Pathology, Ohio State University School of Medicine, Columbus, Ohio 43210, USA.
12
Department of Pediatrics, Ohio State University School of Medicine, Columbus, Ohio 43210, USA.
13
Children's Oncology Group, Arcadia, California 91006, USA.
14
Department of Pediatrics, University of California, San Francisco, California 94143, USA.
15
Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94115, USA.
16
Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, 10117, Germany.
17
Department of Biomedical Informatics, Columbia University, New York, New York 10032, USA.
18
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032, USA.

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.

PMID:
29342136
PMCID:
PMC5931372
DOI:
10.1038/nature25186
[Indexed for MEDLINE]
Free PMC Article

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