title: Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies.
abstract: The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP), which causes DNA damage through perturbation of DNA synthesis. Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment. Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient-derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Nikolas
authors.identifier: http://orcid.org/0000-0001-9468-4543
authors.initials: N
authors.lastname: Herold
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sean G
authors.initials: SG
authors.lastname: Rudd
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Ljungblad
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sanjiv
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ida Hed
authors.initials: IH
authors.lastname: Myrberg
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Cynthia B J
authors.initials: CB
authors.lastname: Paulin
authors.affiliation: Department of Medicine, Center of Hematology and Regenerative Medicine, Karolinska Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Yaser
authors.initials: Y
authors.lastname: Heshmati
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Hagenkort
authors.affiliation: Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Kutzner
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Brent D G
authors.initials: BD
authors.lastname: Page
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: José M
authors.initials: JM
authors.lastname: Calderón-Montaño
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Loseva
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ann-Sofie
authors.initials: AS
authors.lastname: Jemth
authors.affiliation: Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Bulli
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Chemical Biology Consortium, Stockholm, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Axelsson
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Bianca
authors.initials: B
authors.lastname: Tesi
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nicholas C K
authors.identifier: http://orcid.org/0000-0002-9423-964X
authors.initials: NC
authors.lastname: Valerie
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Höglund
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Julia
authors.initials: J
authors.lastname: Bladh
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Elisée
authors.initials: E
authors.lastname: Wiita
authors.affiliation: Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.|Paediatric Blood Disorders, Immunodeficiency and Stem Cell Transplantation, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Sundin
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Uhlin
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Georgios
authors.initials: G
authors.lastname: Rassidakis
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Heyman
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Katja Pokrovskaja
authors.initials: KP
authors.lastname: Tamm
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Warpman-Berglund
authors.affiliation: Department of Medicine, Center of Hematology and Regenerative Medicine, Karolinska Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Julian
authors.initials: J
authors.lastname: Walfridsson
authors.affiliation: Department of Medicine, Center of Hematology and Regenerative Medicine, Karolinska Hospital and Karolinska Institutet, Stockholm, Sweden.|Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Sören
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Dan
authors.initials: D
authors.lastname: Grandér
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Chemical Biology Consortium, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundbäck
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.affiliation: Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Torsten
authors.identifier: http://orcid.org/0000-0001-9597-4112
authors.initials: T
authors.lastname: Schaller
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 / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D020559:Monomeric GTP-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D011379:Prognosis; D000076106:SAM Domain and HD Domain-Containing Protein 1; D054334:Viral Regulatory and Accessory Proteins / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; C513059:VPX protein, Simian immunodeficiency virus; D054334:Viral Regulatory and Accessory Proteins; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins