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SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP.
- Davenne, Tamara (author)
- Klintman, Jenny (author)
-
- Sharma, Sushma (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik,Molekylär Infektionsmedicin, Sverige (MIMS),Andrei Chabes
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- Rigby, Rachel E. (author)
- Blest, Henry T. W. (author)
- Cursi, Chiara (author)
- Bridgeman, Anne (author)
- Dadonaite, Bernadeta (author)
- De Keersmaecker, Kim (author)
- Hillmen, Peter (author)
- Schuh, Anna (author)
- Rehwinkel, Jan (author)
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- (creator_code:org_t)
- Elsevier, 2020
- 2020
- English.
- In: Cell Reports. - : Elsevier. - 2211-1247. ; 31:6
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- BCX-1777
- CyTOF
- Immucillin H
- SAMHD1
- apoptosis
- chronic lymphocytic leukemia
- dGTP
- dNTP
- deoxyguanosine
- forodesine
Publication and Content Type
- ref (subject category)
- art (subject category)
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- Schuh, Anna
- Rehwinkel, Jan
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