SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP

Tamara Davenne,Jenny Klintman,Sushma Sharma,Rachel E Rigby,Henry T.W Blest,Chiara Cursi,Anne Bridgeman,Bernadeta Dadonaite,Kim De Keersmaecker,Peter Hillmen,Andrei Chabes,Anna Schuh,Jan Rehwinkel

doi:10.1016/j.celrep.2020.107640

Abstract

SummaryThe 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.

Highlights

Intracellular deoxyribonucleoside triphosphate concentrations are controlled by dNTP synthesis and degradation. dNTPs are supplied by two pathways known as de novo and salvage
We report that SAMHD1 protected cells against imbalances in dNTP pools
SAMHD1 Protects Cells against dNTP Overload To investigate the role of SAMHD1 in dNTP metabolism, we added equimolar concentrations of dNs to wild-type (WT) or SAMHD1-deficient cells

Summary

Introduction

Intracellular deoxyribonucleoside triphosphate (dNTP) concentrations are controlled by dNTP synthesis and degradation. dNTPs are supplied by two pathways known as de novo and salvage. DNTPs are supplied by two pathways known as de novo and salvage. In the de novo pathway, dNTPs are synthesized from intracellular precursors. The salvage pathway involves uptake of dNs from the extracellular environment, followed by intracellular phosphorylation by cytosolic and mitochondrial kinases to form dNTPs (Eriksson et al, 2002; Inoue, 2017; Reichard, 1988). One enzyme that degrades intracellular dNTPs is the phosphohydrolase SAMHD1, initially identified as an interferon ginducible transcript in dendritic cells (Li et al, 2000). By limiting the supply of dNTPs for the viral reverse transcriptase, SAMHD1 blocks HIV infection in certain cell types (Hrecka et al, 2011; Laguette et al, 2011; Lahouassa et al, 2012; Rehwinkel et al, 2013).

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