2. Academic Validation
  3. SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP

SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP

  • Cell Rep. 2020 May 12;31(6):107640. doi: 10.1016/j.celrep.2020.107640.
Tamara Davenne 1,  Jenny Klintman 2,  Sushma Sharma 3,  Rachel E Rigby 4,  Henry T W Blest 4,  Chiara Cursi 4,  Anne Bridgeman 4,  Bernadeta Dadonaite 5,  Kim De Keersmaecker 6,  Peter Hillmen 7,  Andrei Chabes 3,  Anna Schuh 8,  Jan Rehwinkel 9
Affiliations

Affiliations

  • 1 Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK; Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.
  • 2 Molecular Diagnostic Centre, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
  • 3 Department of Medical Biochemistry and Biophysics and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 901 87 Umeå, Sweden.
  • 4 Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • 5 Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
  • 6 Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.
  • 7 St James' Institute of Oncology, St James' University Hospital, Leeds LS9 7TF, UK.
  • 8 Molecular Diagnostic Centre, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; Department of Oncology, Old Road Campus Research Building, University of Oxford, Oxford OX3 7DQ, UK; Department of Haematology, Oxford University Hospitals NHS Trust, Oxford OX3 7JL, UK.
  • 9 Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK. Electronic address: [email protected].
PMID: 32402273 DOI: 10.1016/j.celrep.2020.107640
Abstract

The anti-leukemia agent forodesine causes cytotoxic overload of intracellular deoxyguanosine triphosphate (dGTP) but is efficacious only in a subset of patients. We report that SAMHD1, a phosphohydrolase degrading deoxyribonucleoside triphosphate (dNTP), protects cells against the effects of dNTP imbalances. SAMHD1-deficient cells induce intrinsic Apoptosis upon provision of deoxyribonucleosides, particularly deoxyguanosine (dG). Moreover, dG and forodesine act synergistically to kill cells lacking SAMHD1. Using mass cytometry, we find that these compounds kill SAMHD1-deficient malignant cells in patients with chronic lymphocytic leukemia (CLL). Normal cells and CLL cells from patients without SAMHD1 mutation are unaffected. We therefore propose to use forodesine as a precision medicine for leukemia, stratifying patients by SAMHD1 genotype or expression.

Keywords

BCX-1777; CyTOF; Immucillin H; SAMHD1; apoptosis; chronic lymphocytic leukemia; dGTP; dNTP; deoxyguanosine; forodesine.

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