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Cancer Cell. 2018 Jul 9;34(1):136-147.e6. doi: 10.1016/j.ccell.2018.06.003.

Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
2
Hervert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, 1212 Amsterdam Avenue, 701 Fairchild Center, New York, NY 10027, USA.
3
Department of Systems Biology, Columbia University, New York, NY 10032, USA.
4
Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin 10117, Germany.
5
Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, 1212 Amsterdam Avenue, 701 Fairchild Center, New York, NY 10027, USA.
6
New York Structural Biology Center, New York, NY 10027, USA.
7
Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, 1212 Amsterdam Avenue, 701 Fairchild Center, New York, NY 10027, USA. Electronic address: ltong@columbia.edu.
8
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA; Department of Pediatrics, Columbia University Medical Center, 1130 St. Nicholas Avenue, ICRC 402, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: af2196@columbia.edu.

Abstract

Activating mutations in the cytosolic 5'-nucleotidase II gene NT5C2 drive resistance to 6-mercaptopurine in acute lymphoblastic leukemia. Here we demonstrate that constitutively active NT5C2 mutations K359Q and L375F reconfigure the catalytic center for substrate access and catalysis in the absence of allosteric activator. In contrast, most relapse-associated mutations, which involve the arm segment and residues along the surface of the inter-monomeric cavity, disrupt a built-in switch-off mechanism responsible for turning off NT5C2. In addition, we show that the C-terminal acidic tail lost in the Q523X mutation functions to restrain NT5C2 activation. These results uncover dynamic mechanisms of enzyme regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies.

KEYWORDS:

6-mercaptopurine; NT5C2; activating mutation; acute lymphoblastic leukemia; allosteric activation; chemotherapy resistance; crystal structure; enzyme regulation; nucleotidase

PMID:
29990496
PMCID:
PMC6049837
[Available on 2019-07-09]
DOI:
10.1016/j.ccell.2018.06.003

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