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SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). (Andrei Chabes)ORCID iD: 0000-0003-2713-5813
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2020 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 31, no 6, article id 107640Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2020. Vol. 31, no 6, article id 107640
Keywords [en]
BCX-1777, CyTOF, Immucillin H, SAMHD1, apoptosis, chronic lymphocytic leukemia, dGTP, dNTP, deoxyguanosine, forodesine
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-170758DOI: 10.1016/j.celrep.2020.107640PubMedID: 32402273OAI: oai:DiVA.org:umu-170758DiVA, id: diva2:1430338
Available from: 2020-05-14 Created: 2020-05-14 Last updated: 2020-05-15Bibliographically approved

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Sharma, SushmaChabes, Andrei
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