{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T07:24:13Z","timestamp":1762068253947,"version":"build-2065373602"},"reference-count":94,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Both bromodomain and extra-terminal domain (BET) proteins and spleen tyrosine kinase (SYK) represent promising targets in diffuse large B-cell (DLBCL) and Burkitt\u2019s lymphoma (BL). We evaluated the anti-lymphoma activity of the isoform-specific bivalent BET inhibitor AZD5153 (AZD) and the pan-BET inhibitor I-BET151 (I-BET) as single agents and in combination with SYK inhibitor Entospletinib (Ento) in vitro. Methods: The effect of the single agents on cell proliferation and metabolic activity was evaluated in two DLBCL and two BL cell lines. Proliferation, metabolic activity, apoptosis, cell cycle and morphology were further investigated after a combined treatment of AZD or I-BET and Ento. RNAseq profiling of combined AZD+Ento treatment was performed in SU-DHL-4 cells. Results: Both BET inhibitors reduced cell proliferation and metabolic activity in a dose- and time-dependent manner. Combined BET and SYK inhibition enhanced the anti-proliferative effect and induced a G0\/G1 cell cycle arrest. SU-DHL-4 demonstrated a pronounced modulation of gene expression by AZD, which was markedly increased by additional SYK inhibition. Functional enrichment analyses identified combination-specific GO terms related to DNA replication and cell division. Genes such as ADGRA2, MYB, TNFRSF11A, S100A10, PLEKHH3, DHRS2 and FOXP1-AS1 were identified as possible key regulators. Conclusion: Simultaneous inhibition of BET and SYK enhanced the anti-proliferative effects, and induced a combination-specific gene expression signature.<\/jats:p>","DOI":"10.3390\/cancers14194691","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T21:23:27Z","timestamp":1664313807000},"page":"4691","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5816-9296","authenticated-orcid":false,"given":"Sina","family":"Sender","sequence":"first","affiliation":[{"name":"Hematology, Oncology, Palliative Medicine, Department of Medicine, Clinic III, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmad Wael","family":"Sultan","sequence":"additional","affiliation":[{"name":"Hematology, Oncology, Palliative Medicine, Department of Medicine, Clinic III, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Palmer","sequence":"additional","affiliation":[{"name":"Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Koczan","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Core Facility Genomics, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anett","family":"Sekora","sequence":"additional","affiliation":[{"name":"Hematology, Oncology, Palliative Medicine, Department of Medicine, Clinic III, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Beck","sequence":"additional","affiliation":[{"name":"Chronix Biomedical GmbH, 37079 Goettingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekkehard","family":"Schuetz","sequence":"additional","affiliation":[{"name":"Chronix Biomedical GmbH, 37079 Goettingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2013-5426","authenticated-orcid":false,"given":"Leila","family":"Taher","sequence":"additional","affiliation":[{"name":"Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, 18057 Rostock, Germany"},{"name":"Institute of Biomedical Informatics, Graz University of Technology, Stremayrgasse 16\/I, 8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7635-9656","authenticated-orcid":false,"given":"Bertram","family":"Brenig","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Medicine, University of Goettingen, 37077 Goettingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg","family":"Fuellen","sequence":"additional","affiliation":[{"name":"Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Junghanss","sequence":"additional","affiliation":[{"name":"Hematology, Oncology, Palliative Medicine, Department of Medicine, Clinic III, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7123-7986","authenticated-orcid":false,"given":"Hugo","family":"Murua Escobar","sequence":"additional","affiliation":[{"name":"Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/20974","article-title":"Structure and ligand of a histone acetyltransferase bromodomain","volume":"399","author":"Dhalluin","year":"1999","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.cell.2012.02.013","article-title":"Histone recognition and large-scale structural analysis of the human bromodomain 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