Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy
Abstract The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic eff...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2020-01-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201910419 |
| _version_ | 1827015239292420096 |
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| author | Sean G Rudd Nikolaos Tsesmetzis Kumar Sanjiv Cynthia BJ Paulin Lakshmi Sandhow Juliane Kutzner Ida Hed Myrberg Sarah S Bunten Hanna Axelsson Si Min Zhang Azita Rasti Petri Mäkelä Si'Ana A Coggins Sijia Tao Sharda Suman Rui M Branca Georgios Mermelekas Elisée Wiita Sun Lee Julian Walfridsson Raymond F Schinazi Baek Kim Janne Lehtiö Georgios Z Rassidakis Katja Pokrovskaja Tamm Ulrika Warpman‐Berglund Mats Heyman Dan Grandér Sören Lehmann Thomas Lundbäck Hong Qian Jan‐Inge Henter Torsten Schaller Thomas Helleday Nikolas Herold |
| author_facet | Sean G Rudd Nikolaos Tsesmetzis Kumar Sanjiv Cynthia BJ Paulin Lakshmi Sandhow Juliane Kutzner Ida Hed Myrberg Sarah S Bunten Hanna Axelsson Si Min Zhang Azita Rasti Petri Mäkelä Si'Ana A Coggins Sijia Tao Sharda Suman Rui M Branca Georgios Mermelekas Elisée Wiita Sun Lee Julian Walfridsson Raymond F Schinazi Baek Kim Janne Lehtiö Georgios Z Rassidakis Katja Pokrovskaja Tamm Ulrika Warpman‐Berglund Mats Heyman Dan Grandér Sören Lehmann Thomas Lundbäck Hong Qian Jan‐Inge Henter Torsten Schaller Thomas Helleday Nikolas Herold |
| author_sort | Sean G Rudd |
| collection | DOAJ |
| description | Abstract The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML. |
| first_indexed | 2024-03-07T17:39:28Z |
| format | Article |
| id | doaj.art-ee94cd1a0d794c99b66c9335300d2f1e |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:19:18Z |
| publishDate | 2020-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-ee94cd1a0d794c99b66c9335300d2f1e2024-10-28T08:54:27ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-01-0112312010.15252/emmm.201910419Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacySean G Rudd0Nikolaos Tsesmetzis1Kumar Sanjiv2Cynthia BJ Paulin3Lakshmi Sandhow4Juliane Kutzner5Ida Hed Myrberg6Sarah S Bunten7Hanna Axelsson8Si Min Zhang9Azita Rasti10Petri Mäkelä11Si'Ana A Coggins12Sijia Tao13Sharda Suman14Rui M Branca15Georgios Mermelekas16Elisée Wiita17Sun Lee18Julian Walfridsson19Raymond F Schinazi20Baek Kim21Janne Lehtiö22Georgios Z Rassidakis23Katja Pokrovskaja Tamm24Ulrika Warpman‐Berglund25Mats Heyman26Dan Grandér27Sören Lehmann28Thomas Lundbäck29Hong Qian30Jan‐Inge Henter31Torsten Schaller32Thomas Helleday33Nikolas Herold34Science for Life Laboratory, Department of Oncology‐Pathology, Karolinska InstitutetChildhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska InstitutetScience for Life Laboratory, Department of Oncology‐Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology‐Pathology, Karolinska InstitutetCenter for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska InstitutetDepartment of Infectious Diseases, Virology, University Hospital HeidelbergChildhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska InstitutetDepartment of Infectious Diseases, Virology, University Hospital HeidelbergChemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska InstitutetScience for Life Laboratory, Department of Oncology‐Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology‐Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology‐Pathology, Karolinska InstitutetDepartment of Pediatrics, Emory University School of MedicineDepartment of Pediatrics, Emory University School of MedicineScience for Life Laboratory, Department of Oncology‐Pathology, Karolinska InstitutetDepartment of Oncology‐Pathology, Science for Life Laboratory, Karolinska InstitutetDepartment of Oncology‐Pathology, Science for Life Laboratory, Karolinska InstitutetScience for Life Laboratory, Department of Oncology‐Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology‐Pathology, Karolinska InstitutetCenter for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska InstitutetDepartment of Pediatrics, Emory University School of MedicineDepartment of Pediatrics, Emory University School of MedicineDepartment of Oncology‐Pathology, Science for Life Laboratory, Karolinska InstitutetDepartment of Oncology‐Pathology, Karolinska InstitutetDepartment of Oncology‐Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology‐Pathology, Karolinska InstitutetChildhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska InstitutetDepartment of Oncology‐Pathology, Karolinska InstitutetCenter for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska InstitutetChemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska InstitutetCenter for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska InstitutetChildhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska InstitutetDepartment of Infectious Diseases, Virology, University Hospital HeidelbergScience for Life Laboratory, Department of Oncology‐Pathology, Karolinska InstitutetChildhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska InstitutetAbstract The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML.https://doi.org/10.15252/emmm.201910419acute myeloid leukaemiachemotherapy resistancedrug synergyprecision medicineSAMHD1 |
| spellingShingle | Sean G Rudd Nikolaos Tsesmetzis Kumar Sanjiv Cynthia BJ Paulin Lakshmi Sandhow Juliane Kutzner Ida Hed Myrberg Sarah S Bunten Hanna Axelsson Si Min Zhang Azita Rasti Petri Mäkelä Si'Ana A Coggins Sijia Tao Sharda Suman Rui M Branca Georgios Mermelekas Elisée Wiita Sun Lee Julian Walfridsson Raymond F Schinazi Baek Kim Janne Lehtiö Georgios Z Rassidakis Katja Pokrovskaja Tamm Ulrika Warpman‐Berglund Mats Heyman Dan Grandér Sören Lehmann Thomas Lundbäck Hong Qian Jan‐Inge Henter Torsten Schaller Thomas Helleday Nikolas Herold Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy EMBO Molecular Medicine acute myeloid leukaemia chemotherapy resistance drug synergy precision medicine SAMHD1 |
| title | Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy |
| title_full | Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy |
| title_fullStr | Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy |
| title_full_unstemmed | Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy |
| title_short | Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy |
| title_sort | ribonucleotide reductase inhibitors suppress samhd1 ara ctpase activity enhancing cytarabine efficacy |
| topic | acute myeloid leukaemia chemotherapy resistance drug synergy precision medicine SAMHD1 |
| url | https://doi.org/10.15252/emmm.201910419 |
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