Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia

Nature Medicine volume 23, pages 250–255 (2017)Cite this article

Subjects

A Corrigendum to this article was published on 06 June 2017

This article has been updated

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 cells1. 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 lacking2,3. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate4,5. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs6, 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 particles7,8—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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: SAMHD1 expression levels are inversely correlated with Ara-C cytotoxicity in AML cell lines.
Figure 2: SAMHD1 counteracts Ara-C toxicity in AML cell lines via hydrolysis of the active metabolite, Ara-CTP.
Figure 3: SAMHD1 contributes to the acquired resistance of AML cells to Ara-C.
Figure 4: SAMHD1 expression in leukemic blasts predicts response to Ara-C-containing therapy in mouse models of AML transplantation and patients with AML.

Similar content being viewed by others

Change history

  • 18 April 2017

    In the version of this article initially published, the Acknowledgements section contained an error: “The WEBs laboratory is supported by the Deutsche Forschungsgemeinschaft grant DFG EXC 1003 (H.S.).” is incorrect. The correct sentence is: “W.E.B.’s laboratory is supported by the Deutsche Forschungsgemeinschaft grant DFG EXC 1003.” The error has been corrected in the HTML and PDF versions of the article.

References

  1. Lamba, J.K. Genetic factors influencing cytarabine therapy. Pharmacogenomics 10, 1657–1674 (2009).

    Article  CAS  Google Scholar 

  2. Burnett, A., Wetzler, M. & Löwenberg, B. Therapeutic advances in acute myeloid leukemia. J. Clin. Oncol. 29, 487–494 (2011).

    Article  Google Scholar 

  3. Löwenberg, B. et al. Cytarabine dose for acute myeloid leukemia. N. Engl. J. Med. 364, 1027–1036 (2011).

    Article  Google Scholar 

  4. Franzolin, E. et al. The deoxynucleotide triphosphohydrolase SAMHD1 is a major regulator of DNA precursor pools in mammalian cells. Proc. Natl. Acad. Sci. USA 110, 14272–14277 (2013).

    Article  CAS  Google Scholar 

  5. Li, N., Zhang, W. & Cao, X. Identification of human homologue of mouse IFN-gamma induced protein from human dendritic cells. Immunol. Lett. 74, 221–224 (2000).

    Article  CAS  Google Scholar 

  6. Kohnken, R., Kodigepalli, K.M. & Wu, L. Regulation of deoxynucleotide metabolism in cancer: novel mechanisms and therapeutic implications. Mol. Cancer 14, 176 (2015).

    Article  Google Scholar 

  7. Hrecka, K. et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474, 658–661 (2011).

    Article  CAS  Google Scholar 

  8. Laguette, N. et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474, 654–657 (2011).

    Article  CAS  Google Scholar 

  9. Dombret, H. & Gardin, C. An update of current treatments for adult acute myeloid leukemia. Blood 127, 53–61 (2016).

    Article  CAS  Google Scholar 

  10. Crow, Y.J. & Rehwinkel, J. Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Hum. Mol. Genet. 18 R2, R130–R136 (2009).

    Article  CAS  Google Scholar 

  11. Clifford, R. et al. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood 123, 1021–1031 (2014).

    Article  CAS  Google Scholar 

  12. Merati, M. et al. Aggressive CD8+ epidermotropic cutaneous T-cell lymphoma associated with homozygous mutation in SAMHD1. JAAD Case Rep 1, 227–229 (2015).

    Article  Google Scholar 

  13. Rentoft, M. et al. Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance. Proc. Natl. Acad. Sci. USA 113, 4723–4728 (2016).

    Article  CAS  Google Scholar 

  14. Lahouassa, H. et al. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat. Immunol. 13, 223–228 (2012).

    Article  CAS  Google Scholar 

  15. Baldauf, H.M. et al. SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells. Nat. Med. 18, 1682–1689 (2012).

    Article  CAS  Google Scholar 

  16. Ballana, E. et al. SAMHD1 specifically affects the antiviral potency of thymidine analog HIV reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 58, 4804–4813 (2014).

    Article  Google Scholar 

  17. Gramberg, T., Sunseri, N. & Landau, N.R. Evidence for an activation domain at the amino terminus of simian immunodeficiency virus Vpx. J. Virol. 84, 1387–1396 (2010).

    Article  CAS  Google Scholar 

  18. Early, A.P., Preisler, H.D., Slocum, H. & Rustum, Y.M. A pilot study of high-dose 1-beta-D-arabinofuranosylcytosine for acute leukemia and refractory lymphoma: clinical response and pharmacology. Cancer Res. 42, 1587–1594 (1982).

    CAS  PubMed  Google Scholar 

  19. Arnold, L.H., Kunzelmann, S., Webb, M.R. & Taylor, I.A. A continuous enzyme-coupled assay for triphosphohydrolase activity of HIV-1 restriction factor SAMHD1. Antimicrob. Agents Chemother. 59, 186–192 (2015).

    Article  Google Scholar 

  20. Huber, A.D. et al. SAMHD1 has differential impact on the efficacies of HIV nucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 58, 4915–4919 (2014).

    Article  Google Scholar 

  21. Goldstone, D.C. et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 480, 379–382 (2011).

    Article  CAS  Google Scholar 

  22. Koharudin, L.M. et al. Structural basis of allosteric activation of sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) by nucleoside triphosphates. J. Biol. Chem. 289, 32617–32627 (2014).

    Article  CAS  Google Scholar 

  23. Yan, J. et al. Tetramerization of SAMHD1 is required for biological activity and inhibition of HIV infection. J. Biol. Chem. 288, 10406–10417 (2013).

    Article  CAS  Google Scholar 

  24. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

  25. Komanduri, K.V. & Levine, R.L. Diagnosis and therapy of acute myeloid leukemia in the era of molecular risk stratification. Annu. Rev. Med. 67, 59–72 (2016).

    Article  CAS  Google Scholar 

  26. Keppler, O.T. et al. Susceptibility of rat-derived cells to replication by human immunodeficiency virus type 1. J. Virol. 75, 8063–8073 (2001).

    Article  CAS  Google Scholar 

  27. Capes-Davis, A. et al. Match criteria for human cell line authentication: where do we draw the line? Int. J. Cancer 132, 2510–2519 (2013).

    Article  CAS  Google Scholar 

  28. Wittmann, S. et al. Phosphorylation of murine SAMHD1 regulates its antiretroviral activity. Retrovirology 12, 103 (2015).

    Article  Google Scholar 

  29. Vick, B. et al. An advanced preclinical mouse model for acute myeloid leukemia using patients' cells of various genetic subgroups and in vivo bioluminescence imaging. PLoS One 10, e0120925 (2015).

    Article  Google Scholar 

  30. Thomas, D., Herold, N., Keppler, O.T., Geisslinger, G. & Ferreirós, N. Quantitation of endogenous nucleoside triphosphates and nucleosides in human cells by liquid chromatography tandem mass spectrometry. Anal. Bioanal. Chem. 407, 3693–3704 (2015).

    Article  CAS  Google Scholar 

  31. Kotchetkov, R. et al. Increased malignant behavior in neuroblastoma cells with acquired multi-drug resistance does not depend on P-gp expression. Int. J. Oncol. 27, 1029–1037 (2005).

    CAS  PubMed  Google Scholar 

  32. Michaelis, M. et al. Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death Dis. 2, e243 (2011).

    Article  CAS  Google Scholar 

  33. Michaelis, M. et al. Identification of flubendazole as potential anti-neuroblastoma compound in a large cell line screen. Sci. Rep. 5, 8202 (2015).

    Article  Google Scholar 

  34. Riccardi, C. & Nicoletti, I. Analysis of apoptosis by propidium iodide staining and flow cytometry. Nat. Protoc. 1, 1458–1461 (2006).

    Article  CAS  Google Scholar 

  35. Oellerich, T. et al. FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation. Blood 125, 1936–1947 (2015).

    Article  CAS  Google Scholar 

  36. Samur, M.K. RTCGAToolbox: a new tool for exporting TCGA Firehose data. PLoS One 9, e106397 (2014).

    Article  Google Scholar 

  37. Heuser, M. et al. MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML. Blood 110, 1639–1647 (2007).

    Article  CAS  Google Scholar 

  38. Goffinet, C., Schmidt, S., Kern, C., Oberbremer, L. & Keppler, O.T. Endogenous CD317/Tetherin limits replication of HIV-1 and murine leukemia virus in rodent cells and is resistant to antagonists from primate viruses. J. Virol. 84, 11374–11384 (2010).

    Article  CAS  Google Scholar 

  39. Beloglazova, N. et al. Nuclease activity of the human SAMHD1 protein implicated in the Aicardi-Goutieres syndrome and HIV-1 restriction. J. Biol. Chem. 288, 8101–8110 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study is dedicated to the memory of Professor Werner Reutter. We are grateful to T. Gramberg (Institute of Clinical and Molecular Virology, FAU Erlangen-Nürnberg, Erlangen, Germany) for providing a codon-optimized SAMHD1 expression construct and I. Jeremias (Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany) for providing AML-393. We thank S. Grothe, Y. Voges and K. Lehr for technical assistance, and A. Ruggieri for graphical artwork. We are grateful to R. Zehner for short tandem repeat (STR) profiling. We acknowledge logistic support by N. Herold for LC–MS/MS analyses in the period September to November 2014 as scientific staff in the laboratory of O.T.K. at Goethe University. F.C. is supported by an EMBO long-term fellowship (1305-2015 and Marie Curie Actions LTFCOFUND2013/GA-2013-609409). W.E.B.'s laboratory is supported by the Deutsche Forschungsgemeinschaft grant DFG EXC 1003. This work was supported in part by the Medical Faculty of the University of Frankfurt (O.T.K.), Hilfe für krebskranke Kinder Frankfurt e.V. (J.C.), the Frankfurter Stiftung für krebskranke Kinder (J.C.), by the LOEWE Program of the State of Hessia (LOEWE Center for Translational Medicine and Pharmacology, Frankfurt)(G.G. and H.S.), the José Carreras Leukämie-Stiftung (J.C.), the Deutsche Forschungsgemeinschaft (KE 742/4-1 (O.T.K.), SFB 1039/Z01 (G.G.)), the NSERC Strategic Network grant IBN (M. Michaelis), the Kent Cancer Trust (M. Michaelis) and the LMU Munich (O.T.K.).

Author information

Author notes

  1. Constanze Schneider, Thomas Oellerich, Hanna-Mari Baldauf and Sarah-Marie Schwarz: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Medical Virology, University of Frankfurt, Frankfurt, Germany

    Constanze Schneider, Hanna-Mari Baldauf, Sarah-Marie Schwarz, Lena Stegmann, Margarethe Martin, Oliver T Keppler & Jindrich Cinatl Jr

  2. Department of Medicine II, Hematology and Oncology,

    Thomas Oellerich, Anjali Cremer, Julian Lohmeyer & Hubert Serve

  3. , Goethe University of Frankfurt, Frankfurt, Germany

    Thomas Oellerich, Anjali Cremer, Julian Lohmeyer & Hubert Serve

  4. Cambridge University Department of Haematology, Cambridge Institute of Medical Research, Cambridge, UK

    Thomas Oellerich & Federico Comoglio

  5. German Cancer Consortium partner site, German Cancer Research Center, Heidelberg, Germany

    Thomas Oellerich & Hubert Serve

  6. Department of Virology, Max von Pettenkofer Institute, Ludwig Maximilian University of Munich, Munich, Germany

    Hanna-Mari Baldauf & Oliver T Keppler

  7. Pharmazentrum frankfurt/ZAFES,

    Dominique Thomas, Gerd Geisslinger & Nerea Ferreirós

  8. , Institute of Clinical Pharmacology, Goethe University of Frankfurt, Frankfurt, Germany

    Dominique Thomas, Gerd Geisslinger & Nerea Ferreirós

  9. Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada

    Robert Flick & Alexander F Yakunin

  10. Institute of Pathology, University Medical Center, Göttingen, Germany

    Hanibal Bohnenberger & Philipp Ströbel

  11. Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany

    Lars Kaderali

  12. Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, UK

    Martin Michaelis

  13. Institute of Molecular Medicine, University Hospital Bonn, Bonn, Germany

    Veit Hornung

  14. Gene Center and Department of Biochemistry, Ludwig Maximilian University of Munich, Munich, Germany

    Veit Hornung

  15. Department of Medicine A (Hematology, Oncology), University Hospital Münster, Germany

    Christoph Schliemann & Wolfgang E Berdel

  16. Gerhard Domagk Institute for Pathology, University Hospital Münster, Germany

    Wolfgang Hartmann & Eva Wardelmann

  17. Senckenberg Institute of Pathology, University of Frankfurt, Frankfurt, Germany

    Martin-Leo Hansmann

  18. Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany

    Gerd Geisslinger

Authors
  1. Constanze Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Oellerich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hanna-Mari Baldauf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarah-Marie Schwarz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dominique Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert Flick
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hanibal Bohnenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lars Kaderali
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lena Stegmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anjali Cremer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Margarethe Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Julian Lohmeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Martin Michaelis
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Veit Hornung
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Christoph Schliemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Wolfgang E Berdel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Wolfgang Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Eva Wardelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Federico Comoglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Martin-Leo Hansmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Alexander F Yakunin
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Gerd Geisslinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Philipp Ströbel
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Nerea Ferreirós
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Hubert Serve
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Oliver T Keppler
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Jindrich Cinatl Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.C. and O.T.K. conceived the study and, together with C.S., T.O., H.-M.B., and S.-M.S., designed, conducted and analyzed the majority of experiments. D.T., R.F., H.B., L.S., M. Martin and F.C. conducted experiments, analyzed data and contributed to discussion. A.C., J.L. (primary AML blasts), M. Michaelis (Ara-C-resistant cell lines) and V.H. (THP-1 KO and control cells) provided crucial reagents and discussion. G.G., M.-L.H., L.K., A.F.Y., P.S., N.F., C.S., W.E.B., W.H., E.W. and H.S. analyzed data and provided discussion. J.C. and O.T.K. wrote and all authors edited the manuscript. Correspondence regarding clinical studies should be addressed to H.S. (hubert.serve@kgu.de).

Corresponding authors

Correspondence to Oliver T Keppler or Jindrich Cinatl Jr.

Ethics declarations

Competing interests

The Johann Wolfgang Goethe-University has filed a patent application, on which C.S., T.O., H.-M.B., S.-M.S., V.H., G.G., H.S., O.T.K. and J.C. are listed as inventors.

Supplementary information

Supplementary Figures and Tables

Supplementary Figures 1–27 and Supplementary Tables 1–5 (PDF 20024 kb)

Supplementary Table 6

AML patient cohort characteristics. (XLSX 20 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schneider, C., Oellerich, T., Baldauf, HM. et al. SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Nat Med 23, 250–255 (2017). https://doi.org/10.1038/nm.4255

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4255

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing