Mechanisms of NT5C2-Mediated Thiopurine Resistance in Acute Lymphoblastic Leukemia
| Autor: | William L. Carroll, Jing Li, Richard J. Heath, Xujie Zhao, Takaya Moriyama, Shuguang Liu, Youming Shao, Aleš Hnízda, Julia Meyer, Jun J. Yang, Wentao Yang |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Purine Cancer Research Nucleotidase activity Thiopurine methyltransferase HEK 293 cells Mutant Endogeny Drug resistance Biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Metabolomics Oncology chemistry 030220 oncology & carcinogenesis Cancer research biology.protein |
| Zdroj: | Molecular Cancer Therapeutics. 18:1887-1895 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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′-nucleotidase 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. |
| Databáze: | OpenAIRE |
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