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bioRxiv · 10.1101/2020.02.17.951517

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

Davenne, T.·Klintman, J.·Sharma, S.·Rigby, R. E.·Cursi, C.·Bridgeman, A.·Dadonaite, B.·De Keersmaecker, K.·Hillmen, P.·Chabes, A.·Schuh, A.·Rehwinkel, J.
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Abstract

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. O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/951517v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@69c367org.highwire.dtl.DTLVardef@19be007org.highwire.dtl.DTLVardef@91156corg.highwire.dtl.DTLVardef@1158ec6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOSupplementary Figure 5.C_FLOATNO Graphical Abstract C_FIG Highlights O_LISAMHD1-deficient cells die upon exposure to deoxyribonucleosides (dNs) C_LIO_LIDeoxyguanosine (dG) is the most toxic dN, inducing apoptosis in cells lacking SAMHD1 C_LIO_LISAMHD1-mutated leukaemic cells can be killed by dG and the PNP-inhibitor forodesine C_LI In BriefSAMHD1 degrades deoxyribonucleoside triphosphates (dNTPs), the building blocks of DNA. Davenne et al. found that SAMHD1 protects cells against dNTP imbalances. Exposure of SAMHD1-deficient cells to deoxyguanosine (dG) results in increased intracellular dGTP levels and subsequent apoptosis. This can be exploited to selectively kill cancer cells that acquired SAMHD1 mutations.

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Davenne, T., Klintman, J., Sharma, S., Rigby, R. E., Cursi, C., Bridgeman, A., Dadonaite, B., De Keersmaecker, K., Hillmen, P., Chabes, A., Schuh, A., Rehwinkel, J.. 2020-02-17. SAMHD1 limits the efficacy of forodesine in leukaemia by protecting cells against cytotoxicity of dGTP. https://doi.org/10.1101/2020.02.17.951517

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