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SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia
2017 Nature America, Inc., part of Springer Nature. All rights reserved.
Constanze Schneider1,17, Thomas Oellerich24,17, Hanna-Mari Baldauf1,5,17, Sarah-Marie Schwarz1,17, Dominique Thomas6, Robert Flick7, Hanibal Bohnenberger8, Lars Kaderali9, Lena Stegmann1, Anjali Cremer2, Margarethe Martin1, Julian Lohmeyer2, Martin Michaelis10, Veit Hornung11,12, Christoph Schliemann13, Wolfgang E Berdel13, Wolfgang Hartmann14, Eva Wardelmann14, Federico Comoglio3, Martin-Leo Hansmann15, Alexander F Yakunin7, Gerd Geisslinger6,16, Philipp Strbel8, Nerea Ferreirs6, Hubert Serve2,4,
Oliver T Keppler1,5 & Jindrich Cinatl Jr1
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 cells1.
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 lacking2,3.
SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate4,5. Althoughit has been postulated that SAMHD1 sensitizes cancer cellsto 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 activitythrough genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles7,8potentiates 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 therapywas 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.
The current backbone of AML therapy is treatment with the cyti-dine analog Ara-C and the anthracycline daunorubicin. Despite a high rate of initial remissions, a substantial fraction of patients with AML relapse and acquire resistance to Ara-C1,9. The prognosis of patients with AML, especially elderly individuals, remains dismal2,9.
Mutations in the SAMHD1 gene, which encodes sterile alpha motif and
histidine-aspartic domain-containing protein 1 (SAMHD1), have been...