Schneider, Constanze and Oellerich, Thomas and Baldauf, Hanna-Mari and Schwarz, Sarah-Marie and Thomas, Dominique and Flick, Robert and Bohnenberger, Hanibal and Kaderali, Lars and Stegmann, Lena and Cremer, Anjali and Martin, Margarethe and Lohmeyer, Julian and Michaelis, Martin and Hornung, Veit and Schliemann, Christoph and Berdel, Wolfgang E and Hartmann, Wolfgang and Wardelmann, Eva and Comoglio, Federico and Hansmann, Martin-Leo and Yakunin, Alexander F and Geisslinger, Gerd and Ströbel, Philipp and Ferreirós, Nerea and Serve, Hubert and Keppler, Oliver T and Cinatl, Jindrich (2016) SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Nature medicine, 23 (2). pp. 250-255.
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. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, 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-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.
RM Therapeutics. Pharmacology
University of Kent
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