ArticleNature medicine2017
SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia.
Article in Nature medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 97 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
97 citing papers in PubMed, 1 synthesis or guideline pooled it, 179 citations in OpenAlex.
- Nelarabine in T-cell acute lymphoblastic leukemia: intracellular metabolism and molecular mode-of-action.Leukemia · 2025Pooled it
- Early peripheral clearance of leukemia-associated immunophenotypes in AML: centralized analysis of a randomized trial.Blood advances · 2020Trial
- Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens.Journal of translational medicine · 2018Trial
- SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia.Blood cancer journal · 2018Trial
- The Role of SAMHD1 in Viral Resistance and Transduction Efficiency Challenges in Pediatric Hematological Malignancies: Mechanistic Insights and Clinical Perspectives.European journal of haematology · 2026Review
- Transition Metal Activation Reframes SAMHD1 Regulation.ACS chemical biology · 2026Article
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Transition metal activation reframes SAMHD1 regulation.bioRxiv : the preprint server for biology · 2026Article
- Allosteric targeting with antiviral nucleotide analogs allows fine-tuning of SAMHD1 dNTPase activity.The Journal of biological chemistry · 2026Article
- IMPDH inhibition enhances cytarabine efficacy in SAMHD1-expressing leukaemia cells via guanine nucleotide depletion.Molecular oncology · 2026Article
- Nucleotide salvage, genome instability, and potential therapeutic applications.Nucleic acids research · 2026Review
- Enhancing the Nucleoside Analog Response with Translational Therapeutic Approaches to Overcome Resistance.Cells · 2026Review
- Continuous assay for the dNTP triphosphohydrolase of activated SAMHD1.Analytical biochemistry · 2026Article
- Cellular pharmacology of fludarabine: molecular determinants of transport and metabolism.Frontiers in pharmacology · 2026Review
- Selective depletion of tumor-associated SAMHD1 enhances chemotherapeutic efficacy and antitumor immune responses.Signal transduction and targeted therapy · 2025Article
- Addition of hydroxyurea (hydroxycarbamide) enhances the efficacy of fludarabine/cytarabine-based salvage regimens against acute myeloid leukaemia.British journal of haematology · 2025Article
- Phenotypic plasticity in a novel set of EGFR tyrosine kinase inhibitor-adapted non-small cell lung cancer cell lines.FEBS open bio · 2025Article
- Purine metabolites regulate leukemic cell sensitivity toward cytarabine.Haematologica · 2025Article
- Effect of NME2 and SAMHD1 genetic polymorphisms involved in Ara-C metabolism on the response to induction chemotherapy in adult acute myeloid leukemia.Journal of the Egyptian National Cancer Institute · 2025Article
- SAMHD1 dysfunction impairs DNA damage response and increases sensitivity to PARP inhibition in chronic lymphocytic leukemia.Scientific reports · 2025Article
37 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
27 authors at 8 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.
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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.