ArticleLeukemia2018
Relapsed acute lymphoblastic leukemia-specific mutations in NT5C2 cluster into hotspots driving intersubunit stimulation.
Article in Leukemia, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 26 citations in OpenAlex.
- Article
- Characterizing and predicting ccRCC-causing missense mutations in Von Hippel-Lindau disease.Human molecular genetics · 2024Article
- AI-Driven Enhancements in Drug Screening and Optimization.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Using Graph-Based Signatures to Guide Rational Antibody Engineering.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia.Cancer discovery · 2022Article
- Systematic evaluation of computational tools to predict the effects of mutations on protein stability in the absence of experimental structures.Briefings in bioinformatics · 2022Article
- mmCSM-PPI: predicting the effects of multiple point mutations on protein-protein interactions.Nucleic acids research · 2021Article
- DynaMut2: Assessing changes in stability and flexibility upon single and multiple point missense mutations.Protein science : a publication of the Protein Society · 2021Article
- Distinguishing between PTEN clinical phenotypes through mutation analysis.Computational and structural biotechnology journal · 2021Article
- Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia.Translational oncology · 2021Review
- mCSM-membrane: predicting the effects of mutations on transmembrane proteins.Nucleic acids research · 2020Article
- mmCSM-AB: guiding rational antibody engineering through multiple point mutations.Nucleic acids research · 2020Article
- Article
- mCSM-PPI2: predicting the effects of mutations on protein-protein interactions.Nucleic acids research · 2019Article
- Review
- Towards personalized chemotherapy of acute lymphoblastic leukemia.Oncotarget · 2018Article
- Emerging Role of Purine Metabolizing Enzymes in Brain Function and Tumors.International journal of molecular sciences · 2018Review
- Review
- Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia.Cancer cell · 2018Article
- Kinact: a computational approach for predicting activating missense mutations in protein kinases.Nucleic acids research · 2018Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Activating mutations in NT5C2, a gene encoding cytosolic purine 5'-nucleotidase (cN-II), confer chemoresistance in relapsed acute lymphoblastic leukemia. Here we show that all mutants became independent of allosteric effects of ATP and thus constitutively active. Structural mapping of mutations described in patients demonstrates that 90% of leukemia-specific allelles directly affect two regulatory hotspots within the cN-II molecule-the helix A region: residues 355-365, and the intersubunit interface: helix B (232-242) and flexible interhelical loop L (400-418). Furthermore, analysis of hetero-oligomeric complexes combining wild-type (WT) and mutant subunits showed that the activation is transmitted from the mutated to the WT subunit. This intersubunit interaction forms structural basis of hyperactive NT5C2 in drug-resistant leukemia in which heterozygous NT5C2 mutation gave rise to hetero-tetramer mutant and WT proteins. This enabled us to define criteria to aid the prediction of NT5C2 drug resistance mutations in leukemia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.