title: SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia.
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. 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.
authors.affiliation: Institute of Medical Virology, University of Frankfurt, Frankfurt, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Department of Medicine II, Hematology and Oncology, Goethe University of Frankfurt, Frankfurt, Germany.|Cambridge University Department of Haematology, Cambridge Institute of Medical Research, Cambridge, UK.|German Cancer Consortium partner site, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.affiliation: Institute of Medical Virology, University of Frankfurt, Frankfurt, Germany.|Max von Pettenkofer Institute, Department of Virology, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Hanna-Mari
authors.identifier: http://orcid.org/0000-0003-0589-697X
authors.initials: HM
authors.lastname: Baldauf
authors.affiliation: Institute of Medical Virology, University of Frankfurt, Frankfurt, Germany.
authors.forename: Sarah-Marie
authors.initials: SM
authors.lastname: Schwarz
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University of Frankfurt, Frankfurt, Germany.
authors.forename: Dominique
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Flick
authors.affiliation: Institute of Pathology, University Medical Center, Göttingen, Germany.
authors.forename: Hanibal
authors.initials: H
authors.lastname: Bohnenberger
authors.affiliation: Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.affiliation: Institute of Medical Virology, University of Frankfurt, Frankfurt, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Stegmann
authors.affiliation: Department of Medicine II, Hematology and Oncology, Goethe University of Frankfurt, Frankfurt, Germany.
authors.forename: Anjali
authors.initials: A
authors.lastname: Cremer
authors.affiliation: Institute of Medical Virology, University of Frankfurt, Frankfurt, Germany.
authors.forename: Margarethe
authors.initials: M
authors.lastname: Martin
authors.affiliation: Department of Medicine II, Hematology and Oncology, Goethe University of Frankfurt, Frankfurt, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Lohmeyer
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.affiliation: Institute of Molecular Medicine, University Hospital Bonn, Bonn, Germany.|Gene Center and Department of Biochemistry, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Department of Medicine A (Hematology, Oncology), University Hospital Münster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schliemann
authors.affiliation: Department of Medicine A (Hematology, Oncology), University Hospital Münster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Gerhard Domagk Institute for Pathology, University Hospital Münster, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hartmann
authors.affiliation: Gerhard Domagk Institute for Pathology, University Hospital Münster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wardelmann
authors.affiliation: Cambridge University Department of Haematology, Cambridge Institute of Medical Research, Cambridge, UK.
authors.forename: Federico
authors.identifier: http://orcid.org/0000-0002-8970-6610
authors.initials: F
authors.lastname: Comoglio
authors.affiliation: Senckenberg Institute of Pathology, University of Frankfurt, Frankfurt, Germany.
authors.forename: Martin-Leo
authors.initials: ML
authors.lastname: Hansmann
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada.
authors.forename: Alexander F
authors.identifier: http://orcid.org/0000-0003-0813-6490
authors.initials: AF
authors.lastname: Yakunin
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University of Frankfurt, Frankfurt, Germany.|Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Institute of Pathology, University Medical Center, Göttingen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University of Frankfurt, Frankfurt, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: Department of Medicine II, Hematology and Oncology, Goethe University of Frankfurt, Frankfurt, Germany.|German Cancer Consortium partner site, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.affiliation: Institute of Medical Virology, University of Frankfurt, Frankfurt, Germany.|Max von Pettenkofer Institute, Department of Virology, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Keppler
authors.affiliation: Institute of Medical Virology, University of Frankfurt, Frankfurt, Germany.
authors.forename: Jindrich
authors.identifier: http://orcid.org/0000-0002-6744-2087
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003630:Daunorubicin / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D011379:Prognosis; D012189:Retrospective Studies; D000076106:SAM Domain and HD Domain-Containing Protein 1; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; C484281:Samhd1 protein, mouse; D020559:Monomeric GTP-Binding Proteins; D003630:Daunorubicin