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

Abstract

Immucillin H, chronic lymphocytic leukaemia 28 29 Running title 30 SAMHD1 protects against dGTP toxicity 31 -2 -Graphical Abstract 32 33 34 Highlights 35 • SAMHD1-deficient cells die upon exposure to deoxyribonucleosides (dNs) 36 • Deoxyguanosine (dG) is the most toxic dN, inducing apoptosis in cells lacking 37 SAMHD1 38 • SAMHD1-mutated leukaemic cells can be killed by dG and the PNP-inhibitor 39 forodesine 40 41 In Brief 42 SAMHD1 degrades deoxyribonucleoside triphosphates (dNTPs), the building blocks 43 of DNA. Davenne et al. found that SAMHD1 protects cells against dNTP imbalances. 44Exposure of SAMHD1-deficient cells to deoxyguanosine (dG) results in increased 45 intracellular dGTP levels and subsequent apoptosis. This can be exploited to 46 selectively kill cancer cells that acquired SAMHD1 mutations. 47 -3 - Summary 48The anti-leukaemia agent forodesine causes cytotoxic overload of intracellular 49 deoxyguanosine triphosphate (dGTP) but is efficacious only in a subset of patients. 50We report that SAMHD1, a phosphohydrolase degrading deoxyribonucleoside 51 triphosphates (dNTPs), protected cells against the effects of dNTP imbalances. 52 SAMHD1-deficient cells induced intrinsic apoptosis upon provision of 53deoxyribonucleosides, particularly deoxyguanosine (dG). Moreover, dG and 54 forodesine acted synergistically to kill cells lacking SAMHD1. Using mass cytometry, 55we found that these compounds killed SAMHD1-deficient malignant cells from patients 56 with chronic lymphocytic leukaemia (CLL). Normal cells and CLL cells from patients 57 without SAMHD1 mutation were unaffected. We therefore propose to use forodesine 58 as a precision medicine for leukaemia, stratifying patients by SAMHD1 genotype or 59 expression. 60

SAMHD1 mutations in mantle cell lymphoma are recurrent and confer in vitro resistance to nucleoside analogues

“…The observation that AML, T-PLL and MCL with altered SAMHD1 expression (either by deletion, mutation or other mechanisms) respond differently might therefore be explained by differences in cell type and by different functional effect depending on type of alteration. A recent article by Davenne and coworkers 19 reported functional and pharmacological effects of SAMHD1 depletion in CLL cells, notably identifying forodesine as a potent agent in cells lacking SAMHD1 and elucidating the underlying 6 mechanism. These results additionally raise the possibility of a targeted use of forodesine in MCL carrying disrupting SAMHD1 mutations.…”