Mechanisms of NT5C2-Mediated Thiopurine Resistance in Acute Lymphoblastic Leukemia
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F19%3A00510254" target="_blank" >RIV/61388963:_____/19:00510254 - isvavai.cz</a>
Result on the web
<a href="https://mct.aacrjournals.org/content/18/10/1887" target="_blank" >https://mct.aacrjournals.org/content/18/10/1887</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1158/1535-7163.MCT-18-1112" target="_blank" >10.1158/1535-7163.MCT-18-1112</a>
Alternative languages
Result language
angličtina
Original language name
Mechanisms of NT5C2-Mediated Thiopurine Resistance in Acute Lymphoblastic Leukemia
Original language description
Relapse remains a formidable challenge for acute lymphoblastic leukemia (ALL). Recently, recurrent mutations in NT5C2 were identified as a common genomic lesion unique in relapsed ALL and were linked to acquired thiopurine resistance. However, molecular mechanisms by which NT5C2 regulates thiopurine cytotoxicity were incompletely understood. To this end, we sought to comprehensively characterize the biochemical and cellular effects of NT5C2 mutations. Compared with wild-type NT5C2, mutant proteins showed elevated 5'-nudeotidase activity with a stark preference of thiopurine metabolites over endogenous purine nucleotides, suggesting neomorphic effects specific to thiopurine metabolism. Expression of mutant NT5C2 mutations also significantly reduced thiopurine uptake in vitro with concomitant increase in efflux of 6-mercaptopurine (MP) metabolites, plausibly via indirect effects on drug transporter pathways. Finally, intracellular metabolomic profiling revealed significant shifts in nucleotide homeostasis induced by mutant NT5C2 at baseline, MP treatment also resulted in global changes in metabolomic profiles with completely divergent effects in cells with mutant versus wild-type NT5C2. Collectively, our data indicated that NT5C2 mutations alter thiopurine metabolism and cellular disposition, but also influence endogenous nucleotide homeostasis and thiopurine-induced metabolomic response. These complex mechanisms contributed to NT5C2-mediated drug resistance in ALL and pointed to potential opportunities for therapeutic targeting in relapsed ALL.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2019
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Molecular Cancer Therapeutics
ISSN
1535-7163
e-ISSN
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Volume of the periodical
18
Issue of the periodical within the volume
10
Country of publishing house
US - UNITED STATES
Number of pages
9
Pages from-to
1887-1895
UT code for WoS article
000489688400021
EID of the result in the Scopus database
2-s2.0-85072848453