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.
Journal article
Cell Rep
12/05/2020
31
BCX-1777, CyTOF, Immucillin H, SAMHD1, apoptosis, chronic lymphocytic leukemia, dGTP, dNTP, deoxyguanosine, forodesine, Animals, Deoxyguanine Nucleotides, Drug Resistance, Neoplasm, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Mice, Mice, Inbred C57BL, Purine Nucleosides, Pyrimidinones, SAM Domain and HD Domain-Containing Protein 1