WFRF:(Wiita Elisee)
Sökning: WFRF:(Wiita Elisee) > Targeting SAMHD1 wi...
Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
-
- Herold, Nikolas (författare)
- Karolinska Institutet
-
- Rudd, Sean G. (författare)
- Karolinska Institutet
-
- Ljungblad, Linda (författare)
- Karolinska Institutet
- visa fler...
- visa färre...
- Karolinska Institutet Karolinska Hosp, Dept Med, Ctr Hematol & Regenerat Med, Stockholm, Sweden;Karolinska Inst, Stockholm, Sweden. (creator_code:org_t)
- 2017-01-09
- 2017
- Engelska.
- Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
- Tidskriftsartikel (refereegranskat)
Abstract
Ämnesord
Stäng
- 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)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). 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(7-9). 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.
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta mer i SwePub
- Av författaren/redakt...
- Herold, Nikolas
- Rudd, Sean G.
- Ljungblad, Linda
- Sanjiv, Kumar
- Myrberg, Ida Hed
- Paulin, Cynthia ...
- visa fler...
- Heshmati, Yaser
- Hagenkort, Anna
- Kutzner, Juliane
- Paget, Brent D. ...
- Calderon-Montano ...
- Loseva, Olga
- Jemth, Ann-Sofie
- Bulli, Lorenzo
- Axelsson, Hanna
- Tesi, Bianca
- Valerie, Nichola ...
- Höglund, Andreas
- Bladh, Julia
- Wiita, Elisee
- Sundin, Mikael
- Uhlin, Michael
- Rassidakis, Geor ...
- Heyman, Mats
- Tamm, Katja Pokr ...
- Warpman-Berglund ...
- Walfridsson, Jul ...
- Lehmann, Sören
- Grander, Dan
- Lundbäck, Thomas
- Kogner, Per
- Henter, Jan-Inge
- Helleday, Thomas
- Schaller, Torste ...
- visa färre...
- Artiklar i publikationen
- Nature Medicine
- Av lärosätet
- Uppsala universitet
- Karolinska Institutet
Sök utanför SwePub
- Sök vidare i:
- Google Book Search
- Google Scholar
Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.
- Copyright © LIBRIS - Nationella bibliotekssystem
- LIBRIS.kb.se
