SAMHD1 limits the efficacy of forodesine in leukaemia by protecting cells against cytotoxicity of dGTP

The anti-leukaemia 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 triphosphates (dNTPs), protected cells against the effects of dNTP imbalances. SAMHD1-deficient cells induced intrinsic apoptosis upon provision of deoxyribonucleosides, particularly deoxyguanosine (dG). Moreover, dG and forodesine acted synergistically to kill cells lacking SAMHD1. Using mass cytometry, we found that these compounds killed SAMHD1-deficient malignant cells from patients with chronic lymphocytic leukaemia (CLL). Normal cells and CLL cells from patients without SAMHD1 mutation were unaffected. We therefore propose to use forodesine as a precision medicine for leukaemia, stratifying patients by SAMHD1 genotype or expression.

Amplification of fluorescent DNA through enzymatic incorporation of a highly emissive deoxyguanosine analogue

A highly emissive thio-analogue of deoxyguanosine triphosphate was synthesized and enzymatically incorporated into DNA. The straightforward amplification of fluorescent DNA by natural polymerases was demonstrated.