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This work was supported by the Swedish Cancer Society (21 1478 Pj) (B.S.), The Swedish Research Council (2019-01705) (B.S.), and The Cancer Society in Stockholm (201323) (B.S.). This research was further supported by grants from the Cathrine Everts Foundation (I.L.), the Stockholm region (FoUI-974942) (N.H.), the Swedish Childhood Cancer Foundation (PR2020-0077) (N.H.), the Swedish Cancer Society (1494 Pj) (N.H.) and (20 1269 PjF) (J.L.), the funds at Radiumhemmet (211143) (N.H.), and the Swedish Research Council (2020-01184) (N.H.) and (2019-04830) (J.L.), the Swedish Medical Association (SLS-961737) (N.H.) and the Francis Crick Institute (I.A.T. and D.S.) which receives its core funding from Cancer Research UK (CC2029 and CC2106), the UK Medical Research Council (CC2029 and CC2106), and the Wellcome Trust (CC2029 and CC2106). V.A. and E.C. are supported by the Ministry of Science and Innovation (PID2021-124048OB-100) (V.A.) and (PID2021-123054OB-I00) (E.C.), the Generalitat de Catalunya Suport Grups de Recerca (AGAUR-Consolidated Research Group) (2021-SGR-01274) (V.A.) and (2021-SGR-01172) (E.C.) and Fundacio la Marato de TV3 (201901-30) (V.A.). This work was also supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grants AI162633 and AI136581) (B.K.) and the National Institute of Mental Health, National Institutes of Health (MH116695) (R.F.S).

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SOX11 is a novel binding partner and endogenous inhibitor of SAMHD1 ara-CTPase activity in mantle cell lymphoma

Publicat a:Blood. 143 (19): 1953-1964 - 2024-05-09 143(19), DOI: 10.1182/blood.2023022241

Autors: Morsy, Mohammad Hamdy Abdelrazak; Lilienthal, Ingrid; Lord, Martin; Merrien, Magali; Wasik, Agata Magdalena; Sureda-Gomez, Marta; Amador, Virginia; Johansson, Henrik J; Lehtio, Janne; Garcia-Torre, Beatriz; Martin-Subero, Jose Ignacio; Tsesmetzis, Nikolaos; Tao, Sijia; Schinazi, Raymond F; Kim, Baek; Sorteberg, Agnes L; Wickstrom, Malin; Sheppard, Devon; Rassidakis, Georgios Z; Taylor, Ian A; Christensson, Birger; Campo, Elias; Herold, Nikolas; Sander, Birgitta

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Resum

Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara -C) resistance in several hematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara -C ef fi cacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMGbox containing protein 11 (SOX11) as a novel direct binding partner and fi rst known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Coimmunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identi fi ed SAMHD1 as the top SOX11 interaction partner, which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar af fi nity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara -C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identi fi ed SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its fi rst known endogenous inhibitor with potentially important implications for clinical therapy strati fi cation.

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