{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:30:14Z","timestamp":1794047414484,"version":"4.8.0"},"reference-count":45,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"2","license":[{"start":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T00:00:00Z","timestamp":1663804800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>Aberrant activity of the SUMOylation pathway has been associated with MYC overexpression and poor prognosis in aggressive B-cell lymphoma (BCL) and other malignancies. Recently developed small-molecule inhibitors of SUMOylation (SUMOi) target the heterodimeric E1 SUMO activation complex (SAE1\/UBA2). Here, we report that activated MYC signaling is an actionable molecular vulnerability in vitro and in a preclinical murine in vivo model of MYC-driven BCL. While SUMOi conferred direct effects on MYC-driven lymphoma cells, SUMO inhibition also resulted in substantial remodeling of various subsets of the innate and specific immunity in vivo. Specifically, SUMOi increased the number of memory B cells as well as cytotoxic and memory T cells, subsets that are attributed a key role within a coordinated anti-tumor immune response. In summary, our data constitute pharmacologic SUMOi as a powerful therapy in a subset of BCL causing massive remodeling of the normal B-cell and T-cell compartment.<\/jats:p>","DOI":"10.3324\/haematol.2022.280995","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T03:15:22Z","timestamp":1663816522000},"page":"555-567","source":"Crossref","is-referenced-by-count":11,"title":["Small-molecule SUMO inhibition for biomarker-informed B-cell lymphoma therapy"],"prefix":"10.3324","volume":"108","author":[{"given":"Uta M.","family":"Demel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Wirth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Schayan","family":"Yousefian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstandina","family":"Isaakidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"D\u00f6nig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlitt","family":"B\u00f6ger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazal","family":"K\u00f6se","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Haas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Schick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2022,9,22]]},"reference":[{"key":"44730","doi-asserted-by":"crossref","unstructured":"Dang CV. MYC on the path to cancer. Cell. 2012; 149(1):22-35.","DOI":"10.1016\/j.cell.2012.03.003"},{"key":"44731","doi-asserted-by":"crossref","unstructured":"Schick M, Habringer S, Nilsson JA, Keller U. Pathogenesis and therapeutic targeting of aberrant MYC expression in haematological cancers. Br J Haematol. 2017; 179(5):724-738.","DOI":"10.1111\/bjh.14917"},{"key":"44732","doi-asserted-by":"crossref","unstructured":"Chen H, Liu H, Qing G. Targeting oncogenic Myc as a strategy for cancer treatment. Signal Transduct Target Ther. 2018; 3:5.","DOI":"10.1038\/s41392-018-0008-7"},{"key":"44733","doi-asserted-by":"crossref","unstructured":"Singh K, Lin J, Zhong Y. c-MYC regulates mRNA translation efficiency and start-site selection in lymphoma. J Exp Med. 2019; 216(7):1509-1524.","DOI":"10.1084\/jem.20181726"},{"key":"44734","doi-asserted-by":"crossref","unstructured":"Ruggero D. The role of Myc-induced protein synthesis in cancer. Cancer Res. 2009; 69(23):8839-8843.","DOI":"10.1158\/0008-5472.CAN-09-1970"},{"key":"44735","doi-asserted-by":"crossref","unstructured":"Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, metabolism, and cancer. Cancer Discov. 2015; 5(10):1024-1039.","DOI":"10.1158\/2159-8290.CD-15-0507"},{"key":"44736","doi-asserted-by":"crossref","unstructured":"Kaelin WG. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005; 5(9):689-698.","DOI":"10.1038\/nrc1691"},{"key":"44737","doi-asserted-by":"crossref","unstructured":"Dhanasekaran R, Deutzmann A, Mahauad-Fernandez WD, Hansen AS, Gouw AM, Felsher DW. The MYC oncogene - the grand orchestrator of cancer growth and immune evasion. Nat Rev Clin Oncol. 2022; 19(1):23-36.","DOI":"10.1038\/s41571-021-00549-2"},{"key":"44738","doi-asserted-by":"crossref","unstructured":"Seeler JS, Dejean A. SUMO and the robustness of cancer. Nat Rev Cancer. 2017; 17(3):184-197.","DOI":"10.1038\/nrc.2016.143"},{"key":"44739","doi-asserted-by":"crossref","unstructured":"Hendriks IA, Vertegaal AC. A comprehensive compilation of SUMO proteomics. Nat Rev Mol Cell Biol. 2016; 17(9):581-595.","DOI":"10.1038\/nrm.2016.81"},{"key":"44740","doi-asserted-by":"crossref","unstructured":"Flotho A, Melchior F. Sumoylation: a regulatory protein modification in health and disease. Annu Rev Biochem. 2013; 82:357-385.","DOI":"10.1146\/annurev-biochem-061909-093311"},{"key":"44741","doi-asserted-by":"crossref","unstructured":"Cappadocia L, Lima CD. Ubiquitin-like protein conjugation: structures, chemistry, and mechanism. Chem Rev. 2018; 118(3):889-918.","DOI":"10.1021\/acs.chemrev.6b00737"},{"key":"44742","doi-asserted-by":"crossref","unstructured":"Kunz K, Piller T, Muller S. SUMO-specific proteases and isopeptidases of the SENP family at a glance. J Cell Sci. 2018; 131(6):jcs211904.","DOI":"10.1242\/jcs.211904"},{"key":"44743","doi-asserted-by":"crossref","unstructured":"Bawa-Khalfe T, Yeh ET. SUMO losing balance: SUMO proteases disrupt SUMO homeostasis to facilitate cancer development and progression. Genes Cancer. 2010; 1(7):748-752.","DOI":"10.1177\/1947601910382555"},{"key":"44744","doi-asserted-by":"crossref","unstructured":"Schick M, Zhang L, Maurer S. Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma. Nat Commun. 2022; 13(1):281.","DOI":"10.1038\/s41467-021-27704-8"},{"key":"44745","doi-asserted-by":"crossref","unstructured":"Driscoll JJ, Pelluru D, Lefkimmiatis K. The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome. Blood. 2010; 115(14):2827-2834.","DOI":"10.1182\/blood-2009-03-211045"},{"key":"44746","doi-asserted-by":"crossref","unstructured":"Sun WC, Hsu PI, Yu HC. The compliance of doctors with viral hepatitis B screening and antiviral prophylaxis in cancer patients receiving cytotoxic chemotherapy using a hospitalbased screening reminder system. PLoS One. 2015; 10(2):e0116978.","DOI":"10.1371\/journal.pone.0116978"},{"key":"44747","doi-asserted-by":"crossref","unstructured":"Decque A, Joffre O, Magalhaes JG. Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing. Nat Immunol. 2016; 17(2):140-149.","DOI":"10.1038\/ni.3342"},{"key":"44748","doi-asserted-by":"crossref","unstructured":"Kumar S, Schoonderwoerd MJA, Kroonen JS. Targeting pancreatic cancer by TAK-981: a SUMOylation inhibitor that activates the immune system and blocks cancer cell cycle progression in a preclinical model. Gut. 2022; 71(11):2266-2283.","DOI":"10.1136\/gutjnl-2021-324834"},{"key":"44749","doi-asserted-by":"crossref","unstructured":"Demel UM, Boger M, Yousefian S. Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer. J Clin Invest. 2022; 132(9):e152383.","DOI":"10.1172\/JCI152383"},{"key":"44750","doi-asserted-by":"crossref","unstructured":"Kessler JD, Kahle KT, Sun T. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science. 2012; 335(6066):348-353.","DOI":"10.1126\/science.1212728"},{"key":"44751","doi-asserted-by":"crossref","unstructured":"Hoellein A, Fallahi M, Schoeffmann S. Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma. Blood. 2014; 124(13):2081-2090.","DOI":"10.1182\/blood-2014-06-584524"},{"key":"44752","doi-asserted-by":"crossref","unstructured":"Biederstadt A, Hassan Z, Schneeweis C. SUMO pathway inhibition targets an aggressive pancreatic cancer subtype. Gut. 2020; 69(8):1472-1482.","DOI":"10.1136\/gutjnl-2018-317856"},{"key":"44753","doi-asserted-by":"crossref","unstructured":"He X, Riceberg J, Soucy T. Probing the roles of SUMOylation in cancer cell biology by using a selective SAE inhibitor. Nat Chem Biol. 2017; 13(11):1164-1171.","DOI":"10.1038\/nchembio.2463"},{"key":"44754","doi-asserted-by":"crossref","unstructured":"Langston SP, Grossman S, England D. Discovery of TAK-981, a first-in-class inhibitor of SUMO-activating enzyme for the treatment of cancer. J Med Chem. 2021; 64(5):2501-2520.","DOI":"10.1021\/acs.jmedchem.0c01491"},{"key":"44755","doi-asserted-by":"crossref","unstructured":"Doffo J, Bamopoulos SA, Kose H. NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer. Proc Natl Acad Sci U S A. 2022; 119(9):e2105691119.","DOI":"10.1073\/pnas.2105691119"},{"key":"44756","doi-asserted-by":"crossref","unstructured":"Casey SC, Baylot V, Felsher DW. The MYC oncogene is a global regulator of the immune response. Blood. 2018; 131(18):2007-2015.","DOI":"10.1182\/blood-2017-11-742577"},{"key":"44757","doi-asserted-by":"crossref","unstructured":"Kubli SP, Berger T, Araujo DV, Siu LL, Mak TW. Beyond immune checkpoint blockade: emerging immunological strategies. Nat Rev Drug Discov. 2021; 20(12):899-919.","DOI":"10.1038\/s41573-021-00155-y"},{"key":"44758","doi-asserted-by":"crossref","unstructured":"Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012; 12(4):269-281.","DOI":"10.1038\/nri3191"},{"key":"44759","doi-asserted-by":"crossref","unstructured":"Borst J, Ahrends T, Babala N, Melief CJM, Kastenmuller W. CD4(+) T cell help in cancer immunology and immunotherapy. Nat Rev Immunol. 2018; 18(10):635-647.","DOI":"10.1038\/s41577-018-0044-0"},{"key":"44760","doi-asserted-by":"crossref","unstructured":"Tay RE, Richardson EK, Toh HC. Revisiting the role of CD4(+) T cells in cancer immunotherapy-new insights into old paradigms. 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Trends Cell Biol. 2020; 30(9):695-704.","DOI":"10.1016\/j.tcb.2020.06.003"},{"key":"44765","doi-asserted-by":"crossref","unstructured":"Lightcap ES, Yu P, Grossman S. A small-molecule SUMOylation inhibitor activates antitumor immune responses and potentiates immune therapies in preclinical models. Sci Transl Med. 2021; 13(611):eaba7791.","DOI":"10.1126\/scitranslmed.aba7791"},{"key":"44766","doi-asserted-by":"crossref","unstructured":"Stoeckius M, Hafemeister C, Stephenson W. Simultaneous epitope and transcriptome measurement in single cells. Nat Methods. 2017; 14(9):865-868.","DOI":"10.1038\/nmeth.4380"},{"key":"44767","doi-asserted-by":"crossref","unstructured":"Finkin S, Hartweger H, Oliveira TY, Kara EE, Nussenzweig MC. Protein amounts of the MYC transcription factor determine germinal center B cell division capacity. Immunity. 2019; 51(2):324-336.","DOI":"10.1016\/j.immuni.2019.06.013"},{"key":"44768","doi-asserted-by":"crossref","unstructured":"Schneider G, Wirth M, Keller U, Saur D. Rationale for MYC imaging and targeting in pancreatic cancer. EJNMMI Res. 2021; 11(1):104.","DOI":"10.1186\/s13550-021-00843-1"},{"key":"44769","doi-asserted-by":"crossref","unstructured":"Llombart V, Mansour MR. Therapeutic targeting of &quot;undruggable&quot; MYC. EBioMedicine. 2022; 75:103756.","DOI":"10.1016\/j.ebiom.2021.103756"},{"key":"44770","doi-asserted-by":"crossref","unstructured":"Nakamura A, Grossman S, Song K. The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation. Blood. 2022; 139(18):2770-2781.","DOI":"10.1182\/blood.2021014267"},{"key":"44771","doi-asserted-by":"crossref","unstructured":"Seton-Rogers S. Oncogenes: driving immune evasion. Nat Rev Cancer. 2018; 18(2):67.","DOI":"10.1038\/nrc.2018.5"},{"key":"44772","doi-asserted-by":"crossref","unstructured":"Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol. 2020; 20(5):294-307.","DOI":"10.1038\/s41577-019-0257-x"},{"key":"44773","doi-asserted-by":"crossref","unstructured":"Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol. 2019; 16(6):356-371.","DOI":"10.1038\/s41571-019-0175-7"},{"key":"44774","doi-asserted-by":"crossref","unstructured":"Pace L, Tempez A, Arnold-Schrauf C. Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory. Science. 2012; 338(6106):532-536.","DOI":"10.1126\/science.1227049"}],"container-title":["Haematologica"],"original-title":[],"link":[{"URL":"https:\/\/haematologica.org\/article\/download\/haematol.2022.280995\/74850","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/haematol.2022.280995\/75276","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/10800\/74850","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:02:23Z","timestamp":1794045743000},"score":1,"resource":{"primary":{"URL":"https:\/\/haematologica.org\/article\/view\/haematol.2022.280995"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,22]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2,1]]}},"URL":"https:\/\/doi.org\/10.3324\/haematol.2022.280995","relation":{},"ISSN":["1592-8721","0390-6078"],"issn-type":[{"value":"1592-8721","type":"electronic"},{"value":"0390-6078","type":"print"}],"subject":[],"published":{"date-parts":[[2022,9,22]]}}}