{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:01:24Z","timestamp":1760144484181,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T00:00:00Z","timestamp":1714176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institutional Fund Projects","award":["IFPRC-217-130-2020"],"award-info":[{"award-number":["IFPRC-217-130-2020"]}]},{"name":"Ministry of Education and King Abdulaziz University, Jeddah, Saudi Arabia","award":["IFPRC-217-130-2020"],"award-info":[{"award-number":["IFPRC-217-130-2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Herpesvirus entry mediator (HVEM) is a molecular switch that can modulate immune responses against cancer. The significance of HVEM as an immune checkpoint target and a potential prognostic biomarker in malignancies is still controversial. This study aims to determine whether HVEM is an immune checkpoint target with inhibitory effects on anti-tumor CD4+ T cell responses in vitro and whether HVEM gene expression is dysregulated in patients with acute lymphocytic leukemia (ALL). HVEM gene expression in tumor cell lines and peripheral blood mononuclear cells (PBMCs) from ALL patients and healthy controls was measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Tumor cells were left untreated (control) or were treated with an HVEM blocker before co-culturing with CD4+ T cells in vitro in a carboxyfluorescein succinimidyl ester (CFSE)-dependent proliferation assay. HVEM expression was upregulated in the chronic myelogenous leukemia cell line (K562) (FC = 376.3, p = 0.086) compared with normal embryonic kidney cells (Hek293). CD4+ T cell proliferation was significantly increased in the HVEM blocker-treated K562 cells (p = 0.0033). Significant HVEM differences were detected in ALL PBMCs compared with the controls, and these were associated with newly diagnosed ALL (p = 0.0011) and relapsed\/refractory (p = 0.0051) B cell ALL (p = 0.0039) patients. A significant differentiation between malignant ALL and the controls was observed in a receiver operating characteristic (ROC) curve analysis with AUC = 0.78 \u00b1 0.092 (p = 0.014). These results indicate that HVEM is an inhibitory molecule that may serve as a target for immunotherapy and a potential ALL biomarker.<\/jats:p>","DOI":"10.3390\/biom14050523","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T08:59:39Z","timestamp":1714553979000},"page":"523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Herpesvirus Entry Mediator as an Immune Checkpoint Target and a Potential Prognostic Biomarker in Myeloid and Lymphoid Leukemia"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5251-559X","authenticated-orcid":false,"given":"Fatemah S.","family":"Basingab","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21859, Saudi Arabia"},{"name":"Immunology Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21859, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reem A.","family":"Alzahrani","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21859, Saudi Arabia"},{"name":"Immunology Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21859, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0416-2723","authenticated-orcid":false,"given":"Aisha A.","family":"Alrofaidi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21859, Saudi Arabia"},{"name":"Immunology Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21859, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2009-3817","authenticated-orcid":false,"given":"Ahmed S.","family":"Barefah","sequence":"additional","affiliation":[{"name":"Hematology Department, Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah 21859, Saudi Arabia"},{"name":"Hematology Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21859, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rawan M.","family":"Hammad","sequence":"additional","affiliation":[{"name":"Hematology Department, Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah 21859, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hadil M.","family":"Alahdal","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science, Princes Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jehan S.","family":"Alrahimi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21859, Saudi Arabia"},{"name":"Immunology Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21859, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0909-6558","authenticated-orcid":false,"given":"Kawther A.","family":"Zaher","sequence":"additional","affiliation":[{"name":"Immunology Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21859, Saudi Arabia"},{"name":"Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21859, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali H.","family":"Algiraigri","sequence":"additional","affiliation":[{"name":"Hematology Department, Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah 21859, Saudi Arabia"},{"name":"Hematology Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21859, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3864-523X","authenticated-orcid":false,"given":"Mai M.","family":"El-Daly","sequence":"additional","affiliation":[{"name":"Special Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21859, Saudi Arabia"},{"name":"Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21859, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2217-1615","authenticated-orcid":false,"given":"Saleh A.","family":"Alkarim","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21859, Saudi Arabia"},{"name":"Embryonic Stem Cells Research Unit and Embryonic and Cancer Stem Cells Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21859, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9599-050X","authenticated-orcid":false,"given":"Alia M.","family":"Aldahlawi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21859, Saudi Arabia"},{"name":"Immunology Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21859, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12943-023-01845-4","article-title":"Beyond the anti-PD-1\/PD-L1 era: Promising role of the BTLA\/HVEM axis as a future target for cancer 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