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Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy
Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical processes and Pharmaceutical Development. Karolinska Institute, Sweden.
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2020 (English)In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, article id e10419Article in journal (Refereed) Published
Abstract [en]

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. © 2020 The Authors. Published under the terms of the CC BY 4.0 license

Place, publisher, year, edition, pages
Blackwell Publishing Ltd , 2020. article id e10419
Keywords [en]
acute myeloid leukaemia, chemotherapy resistance, drug synergy, precision medicine, SAMHD1
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:ri:diva-44100DOI: 10.15252/emmm.201910419Scopus ID: 2-s2.0-85078607361OAI: oai:DiVA.org:ri-44100DiVA, id: diva2:1396862
Note

Funding details: Torsten Söderbergs Stiftelse; Funding details: Alex och Eva Wallströms Stiftelse för Vetenskaplig Forskning och Utbildning, 2018‐02716, 2016‐52575, 2018‐00109, 2017‐00475, 2017‐01287; Funding details: Stiftelsen Lars Hiertas Minne, FO2018‐0002; Funding details: 2019‐01128; Funding details: American Liver Foundation, ALF, 20180318, 20150016, 20150353, K2892‐2016; Funding details: PR2013‐0002, PROF06/001, KP2018‐0005, PR2018‐0016, TJ2017‐0021, PR2015/005, FR2017‐0154, PR2014‐0048, PR2016‐0044, TJ2016‐0040; Funding details: German-Israeli Foundation for Scientific Research and Development, GIF, SCHA1950/1‐1; Funding details: Stockholms Läns Landsting; Funding details: Åke Wiberg Stiftelse, M18‐0012; Funding details: Sveriges Läkarförbund, SMA, SLS‐875361; Funding details: 191112, 171162, 154242, 174122; Funding details: Harald och Greta Jeanssons Stiftelse; Funding details: Vetenskapsrådet, VR, 2012‐5935, 2018‐02114, 2015‐00162, 2013‐3791; Funding details: Märta och Gunnar V. Philipsons Stiftelse; Funding details: Karolinska Institutet, KI, 829‐2009‐6241; Funding details: 2018‐01086; Funding details: M18228; Funding details: CAN 2014/814, CAN 2012/770, CAN 2016/275, CAN 2015/255, CAN 2013/396, CAN 2017/517, CAN 2017/774; Funding details: Stiftelsen Sigurd and Elsa Goljes Minne, LA2018‐0038; Funding details: Foundation for the National Institutes of Health, FNIH, AI136581, GM104198, MH116695; Funding details: Karolinska Institutet, KI, 2016‐50756 & 2018‐01086, 2016‐50273 & 2018‐01573; Funding details: Cancerfonden, 19‐0056‐JIA; Funding text 1: We are grateful to A. Björklund and S. Bengtzén for assistance with primary AML samples. We acknowledge D. Gavhed for administrative assistance. We would like to express our gratitude to NCI's Office of Cancer Genomics (OCG), The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research To Generate Effective Treatments (TARGET). This work was supported by grants from the Swedish Children's Cancer Foundation (TJ2017‐0021 (to S.G.R.); FR2017‐0154 (to H.Q.) PR2017‐0113 (to K.P.T.); PROF06/001, PR2015/005 and KP2018‐0005 (to J.‐I.H); PR2013‐0002 and PR2014‐0048 (to T.H.); TJ2016‐0040, PR2016‐0044 and PR2018‐0016 (to N.H.)), the Swedish Cancer Society (19‐0056‐JIA to S.G.R.; CAN 2017/774 to H.Q.; CAN 2014/814 to Sö.L.; CAN 2012/770 and CAN 2015/255 to T.H.; CAN 2013/396 and CAN 2016/275 to J.‐I.H.; and CAN 2017/517 to N.H.), the Swedish Medical Association (SLS‐875361 to N.H.), the Clas Groschinsky Memorial Foundation (M18228 to N.H.), the Mary Béve Foundation for childhood cancer research (to N.H.), the Harald och Greta Jeanssons Foundation (2018 and 2019 to N.H.), the Åke Wiberg Foundation (M18‐0012 to N.H.), the Lars Hierta Memorial Foundation (FO2018‐0002 to N.H.); the ìShizu Matsumuraî donation (2018‐01086 to N.H.), the Sigurd och Elsa Goljes Memorial Foundation (LA2018‐0038 to N.H.), the Swedish Research Council (2018‐02114 to S.G.R.; 2015‐02498 to Sö.L.; 2011‐3897 to J.‐I.H., and 2012‐5935, 2013‐3791 and 2015‐00162 to T.H.), Radiumhemmet's Research Foundations (171162 to H.Q.; 154242 to G.R.; 174122 to D.G. and 191112 to N.H.), the Torsten and Ragnar Söderberg Foundation (to T.H.), the Stockholm County Council (ALF; 20150353 to Sö.L.; 20150016 and 20180318 to J.‐I.H.; and K2892‐2016 to N.H), the Alex and Eva Wallström Foundation for scientific research and education (2017‐00475 and 2018‐00109 to S.G.R.), the Felix Mindus contribution to Leukemia Research (2016‐52575, 2017‐01287, 2018‐02716 to S.G.R.; 2018‐02715 to N.H.; 2019‐02004 to S.M.Z.), The Loo and Hans Osterman Foundation for Medical Research (2019‐01128 to S.G.R.), the Märta and Gunnar V Philipsons Foundation (to J.‐I.H. and N.H.) and Karolinska Institutet Foundations (2016‐50273 & 2018‐01573 to S.G.R.; and 2016‐50756 & 2018‐01086 to N.H.). This work was further supported by the National Institute of Health (AI136581 and GM104198 to B.K.; MH116695 to R.F.S.). J.K. was supported by the German Research Foundation (SCHA1950/1‐1). Chemical Biology Consortium Sweden is funded by the Swedish Research Council, Science for Life Laboratories and Karolinska Institutet (829‐2009‐6241 to H.A. and T.L.).

Available from: 2020-02-26 Created: 2020-02-26 Last updated: 2020-02-26Bibliographically approved

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