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Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies.
Herold, Nikolas; Rudd, Sean G; Ljungblad, Linda; Sanjiv, Kumar; Myrberg, Ida Hed; Paulin, Cynthia B J; Heshmati, Yaser; Hagenkort, Anna; Kutzner, Juliane; Page, Brent D G; Calderón-Montaño, José M; Loseva, Olga; Jemth, Ann-Sofie; Bulli, Lorenzo; Axelsson, Hanna; Tesi, Bianca; Valerie, Nicholas C K; Höglund, Andreas; Bladh, Julia; Wiita, Elisée; Sundin, Mikael; Uhlin, Michael; Rassidakis, Georgios; Heyman, Mats; Tamm, Katja Pokrovskaja; Warpman-Berglund, Ulrika; Walfridsson, Julian; Lehmann, Sören; Grandér, Dan; Lundbäck, Thomas; Kogner, Per; Henter, Jan-Inge; Helleday, Thomas; Schaller, Torsten.
Afiliação
  • Herold N; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
  • Rudd SG; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Ljungblad L; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
  • Sanjiv K; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Myrberg IH; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
  • Paulin CB; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Heshmati Y; Department of Medicine, Center of Hematology and Regenerative Medicine, Karolinska Hospital and Karolinska Institutet, Stockholm, Sweden.
  • Hagenkort A; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Kutzner J; Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
  • Page BD; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Calderón-Montaño JM; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Loseva O; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Jemth AS; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Bulli L; Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
  • Axelsson H; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Tesi B; Chemical Biology Consortium, Stockholm, Sweden.
  • Valerie NC; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
  • Höglund A; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Bladh J; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Wiita E; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
  • Sundin M; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Uhlin M; Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
  • Rassidakis G; Paediatric Blood Disorders, Immunodeficiency and Stem Cell Transplantation, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
  • Heyman M; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
  • Tamm KP; Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
  • Warpman-Berglund U; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
  • Walfridsson J; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
  • Lehmann S; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
  • Grandér D; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Lundbäck T; Department of Medicine, Center of Hematology and Regenerative Medicine, Karolinska Hospital and Karolinska Institutet, Stockholm, Sweden.
  • Kogner P; Department of Medicine, Center of Hematology and Regenerative Medicine, Karolinska Hospital and Karolinska Institutet, Stockholm, Sweden.
  • Henter JI; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
  • Helleday T; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
  • Schaller T; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Nat Med ; 23(2): 256-263, 2017 Feb.
Article em En | MEDLINE | ID: mdl-28067901
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Protocolos de Quimioterapia Combinada Antineoplásica / Apoptose / Proteínas Monoméricas de Ligação ao GTP / Citarabina / Proteínas Virais Reguladoras e Acessórias / Antimetabólitos Antineoplásicos Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adolescent / Adult / Aged / Aged80 / Animals / Child / Child, preschool / Female / Humans / Infant Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Protocolos de Quimioterapia Combinada Antineoplásica / Apoptose / Proteínas Monoméricas de Ligação ao GTP / Citarabina / Proteínas Virais Reguladoras e Acessórias / Antimetabólitos Antineoplásicos Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adolescent / Adult / Aged / Aged80 / Animals / Child / Child, preschool / Female / Humans / Infant Idioma: En Ano de publicação: 2017 Tipo de documento: Article