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

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

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
12 05 2020
Historique:
received: 13 08 2019
revised: 12 03 2020
accepted: 22 04 2020
entrez: 14 5 2020
pubmed: 14 5 2020
medline: 21 5 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2020.107640 PMID: 32402273 PMC: PMC7225753
pubmed: 32402273
pii: S2211-1247(20)30593-3
doi: 10.1016/j.celrep.2020.107640
pmc: PMC7225753
pii:
doi:

Substances chimiques

Deoxyguanine Nucleotides 0
Purine Nucleosides 0
Pyrimidinones 0
forodesine 426X066ELK
deoxyguanosine triphosphate 8C2O37Y44Q
SAM Domain and HD Domain-Containing Protein 1 EC 3.1.5.-
SAMHD1 protein, human EC 3.1.5.-
Samhd1 protein, mouse EC 3.1.5.-

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

107640

Subventions

Organisme : Medical Research Council
ID : G0902418
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 100954
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 105400/Z/14/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00008
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12025
Pays : United Kingdom

Informations de copyright

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

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Auteurs

Tamara Davenne (T)

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.

Jenny Klintman (J)

Molecular Diagnostic Centre, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.

Sushma Sharma (S)

Department of Medical Biochemistry and Biophysics and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 901 87 Umeå, Sweden.

Rachel E Rigby (RE)

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.

Henry T W Blest (HTW)

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.

Chiara Cursi (C)

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.

Anne Bridgeman (A)

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.

Bernadeta Dadonaite (B)

Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.

Kim De Keersmaecker (K)

Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.

Peter Hillmen (P)

St James' Institute of Oncology, St James' University Hospital, Leeds LS9 7TF, UK.

Andrei Chabes (A)

Department of Medical Biochemistry and Biophysics and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 901 87 Umeå, Sweden.

Anna Schuh (A)

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.

Jan Rehwinkel (J)

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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › SAMHD1 Limits the Efficacy of Forodesine in...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Nucléotides puriques › Nucléotide désoxyguanylique › SAMHD1 Limits the Efficacy of Forodesine in...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › SAMHD1 Limits the Efficacy of Forodesine in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › SAMHD1 Limits the Efficacy of Forodesine in...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Maladie chronique › Leucémie chronique lymphocytaire à cellules B › SAMHD1 Limits the Efficacy of Forodesine in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › SAMHD1 Limits the Efficacy of Forodesine in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › SAMHD1 Limits the Efficacy of Forodesine in...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Nucléoside purique › SAMHD1 Limits the Efficacy of Forodesine in...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Pyrimidinones › SAMHD1 Limits the Efficacy of Forodesine in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de restriction antiviraux › Protéine-1 contenant un domaine SAM et un domaine HD › SAMHD1 Limits the Efficacy of Forodesine in...