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SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia

 
: Schneider, C.; Oellerich, T.; Baldauf, H.-M.; Schwarz, S.-M.; Thomas, D.; Flick, R.; Bohnenberger, H.; Kaderali, L.; Stegmann, L.; Cremer, A.; Martin, M.; Lohmeyer, J.; Michaelis, M.; Hornung, V.; Schliemann, C.; Berdel, W.E.; Hartmann, W.; Wardelmann, E.; Comoglio, F.; Hansmann, M.L.; Yakunin, A.F.; Geisslinger, G.; Ströbel, P.; Ferreiros, N.; Serve, H.; Keppler, O.T.; Cinatl, J.

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Nature Medicine 23 (2017), No.2, pp.250-255
ISSN: 1078-8956
ISSN: 1546-170X
Deutsche Forschungsgemeinschaft DFG
EXC 1003
Deutsche Forschungsgemeinschaft DFG
KE 742/4-1
English
Journal Article
Fraunhofer IME ()

Abstract
The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells'. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking(2,3). SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate(4,5). Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs6, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles(7,8) potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.

: http://publica.fraunhofer.de/documents/N-480862.html