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Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML

Author

Listed:
  • Thomas Oellerich

    (Goethe University of Frankfurt
    German Cancer Consortium/German Cancer Research Center
    Frankfurt Cancer Institute, Goethe University Frankfurt)

  • Constanze Schneider

    (Goethe University of Frankfurt
    Frankfurt Cancer Institute, Goethe University Frankfurt
    University of Frankfurt)

  • Dominique Thomas

    (Goethe University of Frankfurt)

  • Kirsten M. Knecht

    (Yale University)

  • Olga Buzovetsky

    (Yale University)

  • Lars Kaderali

    (University Medicine Greifswald)

  • Christoph Schliemann

    (University Hospital Münster)

  • Hanibal Bohnenberger

    (University Medical Center)

  • Linus Angenendt

    (University Hospital Münster)

  • Wolfgang Hartmann

    (University Hospital Münster)

  • Eva Wardelmann

    (University Hospital Münster)

  • Tamara Rothenburger

    (University of Frankfurt)

  • Sebastian Mohr

    (Goethe University of Frankfurt)

  • Sebastian Scheich

    (Goethe University of Frankfurt)

  • Federico Comoglio

    (Cambridge University)

  • Anne Wilke

    (Goethe University of Frankfurt)

  • Philipp Ströbel

    (University Medical Center)

  • Hubert Serve

    (Goethe University of Frankfurt
    German Cancer Consortium/German Cancer Research Center
    Frankfurt Cancer Institute, Goethe University Frankfurt)

  • Martin Michaelis

    (University of Kent)

  • Nerea Ferreirós

    (Goethe University of Frankfurt)

  • Gerd Geisslinger

    (Goethe University of Frankfurt
    Project group Translational Medicine and Pharmacology (TMP))

  • Yong Xiong

    (Yale University)

  • Oliver T. Keppler

    (University of Frankfurt
    LMU München)

  • Jindrich Cinatl

    (University of Frankfurt)

Abstract

Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia.

Suggested Citation

  • Thomas Oellerich & Constanze Schneider & Dominique Thomas & Kirsten M. Knecht & Olga Buzovetsky & Lars Kaderali & Christoph Schliemann & Hanibal Bohnenberger & Linus Angenendt & Wolfgang Hartmann & Ev, 2019. "Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11413-4
    DOI: 10.1038/s41467-019-11413-4
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    Cited by:

    1. Oliver J. Acton & Devon Sheppard & Simone Kunzelmann & Sarah J. Caswell & Andrea Nans & Ailidh J. O. Burgess & Geoff Kelly & Elizabeth R. Morris & Peter B. Rosenthal & Ian A. Taylor, 2024. "Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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