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

Tamara Davenne; Jenny Klintman; Sushma Sharma; Rachel E Rigby; Henry T W Blest; Chiara Cursi; Anne Bridgeman; Bernadeta Dadonaite; Kim De Keersmaecker; Peter Hillmen; Andrei Chabes; Anna Schuh; Jan Rehwinkel

doi:10.1016/j.celrep.2020.107640

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.

Authors

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: jan.rehwinkel@imm.ox.ac.uk.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Deoxyguanine Nucleotides / metabolism*
Drug Resistance, Neoplasm
Female
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
Male
Mice
Mice, Inbred C57BL
Purine Nucleosides / pharmacology*
Pyrimidinones / pharmacology*
SAM Domain and HD Domain-Containing Protein 1 / metabolism*

Substances

Deoxyguanine Nucleotides
Purine Nucleosides
Pyrimidinones
forodesine
deoxyguanosine triphosphate
SAM Domain and HD Domain-Containing Protein 1
SAMHD1 protein, human
Samhd1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding