RESUMEN
Sterile alpha motif and histidine-aspartic acid domain containing protein-1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) hydrolase that controls dNTP pools and detoxifies cancer cells of chemotherapy metabolites. TH6342 is a recently reported small molecule inhibitor of SAMHD1 that interacts with the protein in vitro and non-competitively prevents dimerisation, a prerequisite for catalysis. The binding site of TH6342 on SAMHD1 is currently unknown. In the present study we demonstrate that the N-terminal SAM domain of SAMHD1 is not required for inhibition by TH6342.
RESUMEN
SAMHD1 is a dNTP triphosphohydrolase governing nucleotide pool homeostasis and can detoxify chemotherapy metabolites controlling their clinical responses. To understand SAMHD1 biology and investigate the potential of targeting SAMHD1 as neoadjuvant to current chemotherapies, we set out to discover selective small-molecule inhibitors. Here, we report a discovery pipeline encompassing a biochemical screening campaign and a set of complementary biochemical, biophysical, and cell-based readouts for rigorous characterization of the screen output. The identified small molecules, TH6342 and analogs, accompanied by inactive control TH7126, demonstrated specific, low µM potency against both physiological and oncology-drug-derived substrates. By coupling kinetic studies with thermal shift assays, we reveal the inhibitory mechanism of TH6342 and analogs, which engage pre-tetrameric SAMHD1 and deter oligomerization and allosteric activation without occupying nucleotide-binding pockets. Altogether, our study diversifies inhibitory modes against SAMHD1, and the discovery pipeline reported herein represents a thorough framework for future SAMHD1 inhibitor development.
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Cytotoxic chemotherapy remains a key modality in cancer treatment. These therapies, successfully used for decades, continue to transform the lives of cancer patients daily. With the high attrition rate of current oncology drug development, combined with the knowledge that most new therapies do not displace standard-of-care treatments and that many healthcare systems cannot afford these new therapies; cytotoxic chemotherapies will remain an important component of cancer therapy for many years to come. The clinical value of these therapies is often under-appreciated within the pre-clinical cancer research community, where this diverse class of agents are often grouped together as non-specific cellular poisons killing tumor cells based solely upon proliferation rate; however, this is inaccurate. This review article seeks to reaffirm the importance of focusing research efforts upon improving our basic understanding of how these drugs work, discussing their ability to target pan-essential pathways in cancer cells, the relationship of this to the chemotherapeutic window, and highlighting basic science approaches that can be employed towards refining their use.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Oncología MédicaRESUMEN
The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of DNA are dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic DNA lesions in cancer cells. These same pathways also activate antimetabolites, an important group of chemotherapies that disrupt both nucleotide and DNA metabolism to induce DNA damage in cancer cells. Thus, dNTP metabolic enzymes can also be targeted to refine the use of these chemotherapeutics, many of which remain standard of care in common cancers. In this review article, we will discuss both these approaches exemplified by the enzymes MTH1, MTHFD2 and SAMHD1. © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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Neoplasias , Humanos , Neoplasias/patología , Nucleótidos/metabolismo , Daño del ADN , Reparación del ADNRESUMEN
Objective: The survival and clinicopathological significance of desmoglein 2 (DSG2) in various cancers is controversial. Thus, we performed this systematic review and meta-analysis to explore the preliminary prognostic value of DSG2. Methods: Eligible studies were identified from databases including PubMed, the Cochrane Library, Embase, Web of Science and Scopus. Hand searches were also conducted in relevant bibliographies. We then extracted and pooled hazard ratio (HR) of overall survival (OS) and odds ratio (OR) of clinicopathological features. Results: A total of 11 eligible studies containing 1,488 patients were included. Our results demonstrated that in non-small cell lung cancer (NSCLC), high DSG2 expression is associated with poor OS. However, in digestive system cancer and female reproductive system cancer, there were no statistically significant associations between OS and DSG2. Conclusions: Based on the findings of this study, high DSG2 expression is associated with worse prognosis in patients with NSCLC, and thus DSG2 expression could be a biomarker for prognosis in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Femenino , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Pronóstico , Desmogleína 2/genética , Neoplasias Pulmonares/metabolismo , Biomarcadores de Tumor/análisisRESUMEN
Asparaginase depletes extracellular asparagine in the blood and is an important treatment for acute lymphoblastic leukemia (ALL) due to asparagine auxotrophy of ALL blasts. Unfortunately, resistance occurs and has been linked to expression of the enzyme asparagine synthetase (ASNS), which generates asparagine from intracellular sources. Although TP53 is the most frequently mutated gene in cancer overall, TP53 mutations are rare in ALL. However, TP53 mutation is associated with poor therapy response and occurs at higher frequency in relapsed ALL. The mutant p53-reactivating compound APR-246 (Eprenetapopt/PRIMA-1Met) is currently being tested in phase II and III clinical trials in several hematological malignancies with mutant TP53. Here we present CEllular Thermal Shift Assay (CETSA) data indicating that ASNS is a direct or indirect target of APR-246 via the active product methylene quinuclidinone (MQ). Furthermore, combination treatment with asparaginase and APR-246 resulted in synergistic growth suppression in ALL cell lines. Our results thus suggest a potential novel treatment strategy for ALL.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Asparaginasa/farmacología , Proliferación Celular/efectos de los fármacos , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Quinuclidinas/farmacología , Proteína p53 Supresora de Tumor/agonistas , Ligasas de Carbono-Nitrógeno con Glutamina como Donante de Amida-N/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Ganciclovir (GCV) is the first-line therapy against human cytomegalovirus (HCMV), a widespread infection that is particularly dangerous for immunodeficient individuals. Closely resembling deoxyguanosine triphosphate, the tri-phosphorylated metabolite of GCV (GCV-TP) is preferentially incorporated by the viral DNA polymerase, thereby terminating chain extension and, eventually, viral replication. However, the treatment outcome of GCV varies greatly among individuals, therefore warranting better understanding of its metabolism. Here we show that NUDT15, a Nudix hydrolase known to metabolize thiopurine triphosphates, can similarly hydrolyze GCV-TP through biochemical studies and co-crystallization of the NUDT15/GCV-TP complex. More critically, GCV efficacy was potentiated in HCMV-infected cells following NUDT15 depletion by RNAi or inhibition by an in-house-developed, nanomolar NUDT15 inhibitor, TH8321, suggesting that pharmacological targeting of NUDT15 is a possible avenue to improve existing anti-HCMV regimens. Collectively, the data further implicate NUDT15 as a broad-spectrum metabolic regulator of nucleoside analog therapeutics, such as thiopurines and GCV.
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Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , Ganciclovir/farmacología , Pirofosfatasas/metabolismo , Antivirales/química , Línea Celular Tumoral , Femenino , Ganciclovir/química , Humanos , Hidrólisis , Pruebas de Sensibilidad Microbiana , Proteínas Recombinantes/metabolismoRESUMEN
Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a pivotal regulator of intracellular deoxynucleoside triphosphate (dNTP) pools, as this enzyme can hydrolyze dNTPs into their corresponding nucleosides and inorganic triphosphates. Due to its critical role in nucleotide metabolism, its association to several pathologies, and its role in therapy resistance, intense research is currently being carried out for a better understanding of both the regulation and cellular function of this enzyme. For this reason, development of simple and inexpensive high-throughput amenable methods to probe small molecule interaction with SAMHD1, such as allosteric regulators, substrates, or inhibitors, is vital. To this purpose, the enzyme-coupled malachite green assay is a simple and robust colorimetric assay that can be deployed in a 384-microwell plate format allowing the indirect measurement of SAMHD1 activity. As SAMHD1 releases the triphosphate group from nucleotide substrates, we can couple a pyrophosphatase activity to this reaction, thereby producing inorganic phosphate, which can be quantified by the malachite green reagent through the formation of a phosphomolybdate malachite green complex. Here, we show the application of this methodology to characterize known inhibitors of SAMHD1 and to decipher the mechanisms involved in SAMHD1 catalysis of non-canonical substrates and regulation by allosteric activators, exemplified by nucleoside-based anticancer drugs. Thus, the enzyme-coupled malachite green assay is a powerful tool to study SAMHD1, and furthermore, could also be utilized in the study of several enzymes which release phosphate species.
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Pruebas de Enzimas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Proteína 1 que Contiene Dominios SAM y HD/genética , HumanosRESUMEN
The enzyme NUDT15 efficiently hydrolyzes the active metabolites of thiopurine drugs, which are routinely used for treating cancer and inflammatory diseases. Loss-of-function variants in NUDT15 are strongly associated with thiopurine intolerance, such as leukopenia, and preemptive NUDT15 genotyping has been clinically implemented to personalize thiopurine dosing. However, understanding the molecular consequences of these variants has been difficult, as no structural information was available for NUDT15 proteins encoded by clinically actionable pharmacogenetic variants because of their inherent instability. Recently, the small molecule NUDT15 inhibitor TH1760 has been shown to sensitize cells to thiopurines, through enhanced accumulation of 6-thio-guanine in DNA. Building upon this, we herein report the development of the potent and specific NUDT15 inhibitor, TH7755. TH7755 demonstrates a greatly improved cellular target engagement and 6-thioguanine potentiation compared with TH1760, while showing no cytotoxicity on its own. This potent inhibitor also stabilized NUDT15, enabling analysis by X-ray crystallography. We have determined high-resolution structures of the clinically relevant NUDT15 variants Arg139Cys, Arg139His, Val18Ile, and V18_V19insGlyVal. These structures provide clear insights into the structural basis for the thiopurine intolerance phenotype observed in patients carrying these pharmacogenetic variants. These findings will aid in predicting the effects of new NUDT15 sequence variations yet to be discovered in the clinic.
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Mutación , Pirofosfatasas/antagonistas & inhibidores , Pirofosfatasas/genética , Tioguanina/química , Tioguanina/farmacología , Cristalografía por Rayos X , Modelos Moleculares , Conformación Proteica , Pirofosfatasas/químicaRESUMEN
OBJECTIVE: Combinations of pharmacological agents are essential for disease control and prevention, offering many advantages over monotherapies, with one of these being drug synergy. The state-of-the-art method to profile drug synergy in preclinical research is by using dose-response matrices in disease-appropriate models, however this approach is frequently labour intensive and cost-ineffective, particularly when performed in a medium- to high-throughput fashion. Thus, in this study, we set out to optimise a parameter of this methodology, determining the minimal matrix size that can be used to robustly detect and quantify synergy between two drugs. RESULTS: We used a drug matrix reduction workflow that allowed the identification of a minimal drug matrix capable of robustly detecting and quantifying drug synergy. These minimal matrices utilise substantially less reagents and data processing power than their typically used larger counterparts. Focusing on the antileukemic efficacy of the chemotherapy combination of cytarabine and inhibitors of ribonucleotide reductase, we could show that detection and quantification of drug synergy by three common synergy models was well-tolerated despite reducing matrix size from 8 × 8 to 4 × 4. Overall, the optimisation of drug synergy scoring as presented here could inform future medium- to high-throughput drug synergy screening strategies in pre-clinical research.
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Ensayos Analíticos de Alto Rendimiento , Preparaciones Farmacéuticas , Sinergismo Farmacológico , Quimioterapia CombinadaRESUMEN
The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.
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Pirofosfatasas/antagonistas & inhibidores , Pirofosfatasas/metabolismo , Sitios de Unión , Línea Celular , Diseño de Fármacos , Desarrollo de Medicamentos , Escherichia coli , Humanos , Pirofosfatasa Inorgánica/antagonistas & inhibidores , Pirofosfatasa Inorgánica/genética , Pirofosfatasa Inorgánica/metabolismo , Modelos Moleculares , Unión Proteica , Conformación Proteica , Pirofosfatasas/química , Pirofosfatasas/genética , Relación Estructura-ActividadRESUMEN
Reactive oxygen species (ROS) oxidize nucleotide triphosphate pools (e.g., 8-oxodGTP), which may kill cells if incorporated into DNA. Whether cancers avoid poisoning from oxidized nucleotides by preventing incorporation via the oxidized purine diphosphatase MTH1 remains under debate. Also, little is known about DNA polymerases incorporating oxidized nucleotides in cells or how oxidized nucleotides in DNA become toxic. Here we show that replacement of one of the main DNA replicases in human cells, DNA polymerase delta (Pol δ), with an error-prone variant allows increased 8-oxodG accumulation into DNA following treatment with TH588, a dual MTH1 inhibitor and microtubule targeting agent. The resulting elevated genomic 8-oxodG correlated with increased cytotoxicity of TH588. Interestingly, no substantial perturbation of replication fork progression was observed, but rather mitotic progression was impaired and mitotic DNA synthesis triggered. Reducing mitotic arrest by reversin treatment prevented accumulation of genomic 8-oxodG and reduced cytotoxicity of TH588, in line with the notion that mitotic arrest is required for ROS buildup and oxidation of the nucleotide pool. Furthermore, delayed mitosis and increased mitotic cell death was observed following TH588 treatment in cells expressing the error-prone but not wild-type Pol δ variant, which is not observed following treatments with antimitotic agents. Collectively, these results link accumulation of genomic oxidized nucleotides with disturbed mitotic progression. SIGNIFICANCE: These findings uncover a novel link between accumulation of genomic 8-oxodG and perturbed mitotic progression in cancer cells, which can be exploited therapeutically using MTH1 inhibitors.See related commentary by Alnajjar and Sweasy, p. 3459.
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8-Hidroxi-2'-Desoxicoguanosina , Monoéster Fosfórico Hidrolasas , Enzimas Reparadoras del ADN/genética , Genómica , Humanos , Mitosis/genética , Monoéster Fosfórico Hidrolasas/genética , Pirimidinas/farmacologíaRESUMEN
The cell cycle is a highly conserved process involving the coordinated separation of a single cell into two daughter cells. To relate transcriptional regulation across the cell cycle with oscillatory changes in protein abundance and activity, we carried out a proteome- and phospho-proteome-wide mass spectrometry profiling. We compared protein dynamics with gene transcription, revealing many transcriptionally regulated G2 mRNAs that only produce a protein shift after mitosis. Integration of CRISPR/Cas9 survivability studies further highlighted proteins essential for cell viability. Analyzing the dynamics of phosphorylation events and protein solubility dynamics over the cell cycle, we characterize predicted phospho-peptide motif distributions and predict cell cycle-dependent translocating proteins, as exemplified by the S-adenosylmethionine synthase MAT2A. Our study implicates this enzyme in translocating to the nucleus after the G1/S-checkpoint, which enables epigenetic histone methylation maintenance during DNA replication. Taken together, this data set provides a unique integrated resource with novel insights on cell cycle dynamics.
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Ciclo Celular/genética , Perfilación de la Expresión Génica , Proteínas de Neoplasias/genética , Núcleo Celular/metabolismo , Células HeLa , Humanos , Proteínas de Neoplasias/metabolismo , Fosforilación , Transporte de Proteínas , Proteoma/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Fracciones Subcelulares/metabolismo , Transcriptoma/genéticaRESUMEN
The deoxycytidine analogue cytarabine (ara-C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara-C efficacy by hydrolysing the active triphosphate metabolite ara-CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1-mediated barrier to ara-C efficacy in primary blasts and mouse models of AML, displaying SAMHD1-dependent synergy with ara-C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara-CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara-C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML.
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Citarabina/farmacología , Leucemia Mieloide Aguda , Pirofosfatasas/metabolismo , Ribonucleótido Reductasas/antagonistas & inhibidores , Proteína 1 que Contiene Dominios SAM y HD/metabolismo , Animales , Trifosfato de Arabinofuranosil Citosina/metabolismo , RatonesRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Sterile alpha motif and histidine/aspartic acid domain containing protein 1 (SAMHD1) limits the efficacy of cytarabine (ara-C) used in AML by hydrolyzing its active metabolite ara-CTP and thus represents a promising therapeutic target. SAMHD1 has also been implicated in DNA damage repair that may impact DNA damage-inducing therapies such as anthracyclines, during induction therapy. To determine whether SAMHD1 limits ara-C efficacy during induction or consolidation therapy, SAMHD1 protein levels were assessed in two patient cohorts of de novo AML from The University of Texas MD Anderson Cancer Center (USA) and the National University Hospital (Singapore), respectively, using immunohistochemistry and tissue microarrays. SAMHD1 was expressed at a variable level by AML blasts but not in a broad range of normal hematopoietic cells in reactive bone marrows. A sizeable patient subset with low SAMHD1 expression (<25% of positive blasts) was identified, which was significantly associated with longer event-free (EFS) and overall (OS) survival in patients receiving high-dose cytarabine (HDAC) during consolidation. Therefore, evaluation of SAMHD1 expression level in AML blasts at diagnosis, may stratify patient groups for future clinical trials combining HDAC with novel SAMHD1 inhibitors as consolidation therapy.
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Biomarcadores de Tumor , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Proteína 1 que Contiene Dominios SAM y HD/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/patología , Terapia Combinada , Quimioterapia de Consolidación , Citarabina/administración & dosificación , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Proteína 1 que Contiene Dominios SAM y HD/metabolismo , Adulto JovenRESUMEN
Antimetabolites, in particular nucleobase and nucleoside analogues, are cytotoxic drugs that, starting from the small field of paediatric oncology, in combination with other chemotherapeutics, have revolutionised clinical oncology and transformed cancer into a curable disease. However, even though combination chemotherapy, together with radiation, surgery and immunotherapy, can nowadays cure almost all types of cancer, we still fail to achieve this for a substantial proportion of patients. The understanding of differences in metabolism, pharmacokinetics, pharmacodynamics, and tumour biology between patients that can be cured and patients that cannot, builds the scientific basis for rational therapy improvements. Here, we summarise current knowledge of how tumour-specific and patient-specific factors can dictate resistance to nucleobase/nucleoside analogues, and which strategies of re-sensitisation exist. We revisit well-established hurdles to treatment efficacy, like the blood-brain barrier and reduced deoxycytidine kinase activity, but will also discuss the role of novel resistance factors, such as SAMHD1. A comprehensive appreciation of the complex mechanisms that underpin the failure of chemotherapy will hopefully inform future strategies of personalised medicine.
RESUMEN
With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Progestinas/metabolismo , Pirofosfatasas/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Adenosina Difosfato Ribosa/metabolismo , Adenosina Trifosfato/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Femenino , Células HL-60 , Humanos , Estructura Molecular , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , Interferencia de ARN , Especificidad por SustratoRESUMEN
Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) is a (deoxy)guanosine triphosphate (dGTP/GTP)-activated deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase involved in cellular dNTP homoeostasis. Mutations in SAMHD1 have been associated with the hyperinflammatory disease Aicardi-Goutières syndrome (AGS). SAMHD1 also limits cells' permissiveness to infection with diverse viruses, including human immunodeficiency virus (HIV-1), and controls endogenous retroviruses. Increasing evidence supports the role of SAMHD1 as a tumor suppressor. However, SAMHD1 also can act as a resistance factor to nucleoside-based chemotherapies by hydrolyzing their active triphosphate metabolites, thereby reducing response of various malignancies to these anticancer drugs. Hence, informed cancer therapies must take into account the ambiguous properties of SAMHD1 as both an inhibitor of uncontrolled proliferation and a resistance factor limiting the efficacy of anticancer treatments. Here, we provide evidence that SAMHD1 is a double-edged sword for patients with acute myelogenous leukemia (AML). Our time-dependent analyses of The Cancer Genome Atlas (TCGA) AML cohort indicate that high expression of SAMHD1, even though it critically limits the efficacy of high-dose ara-C therapy, might be associated with more favorable disease progression.