{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T19:19:27Z","timestamp":1787771967650,"version":"build-2784847793"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"Abstract<\/jats:title>\n \n Background:<\/jats:title>\n Myelodysplastic syndrome (MDS) is a clonal hematologic disorder that requires the integration of morphologic, cytogenetic, hematologic, and clinical findings for a successful diagnosis. Trying to find ancillary tests such as biomarkers improve the diagnosis process. Several studies showed that a disordered immune system is associated with MDS. The chronic activated innate immune system, particularly the Toll-like receptors (TLRs) pathway could be involved in the induction of the inflammation.<\/jats:p>\n <\/jats:sec>\n \n Materials and Methods:<\/jats:title>\n \n In the present study, we investigated the expression of\n TLR2, TLR4<\/jats:italic>\n , and\n IRAK4<\/jats:italic>\n in bone marrow (BM) of MDS patients, the leukemia group, and the healthy group. For this purpose, we assessed the expression of\n TLR2, TLR4<\/jats:italic>\n , and\n IRAK4<\/jats:italic>\n by real time-PCR.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n In line with new findings, we demonstrated that the expression of\n TLR2, TLR4<\/jats:italic>\n , and\n IRAK4<\/jats:italic>\n significantly increased in MDS BM compared with the healthy group. Moreover,\n IRAK4<\/jats:italic>\n expression raised significantly in MDS patients compared with other studied hematologic neoplasms. Also, the expression levels of\n TLR2<\/jats:italic>\n and\n TLR4<\/jats:italic>\n significantly increased in MDS in comparison to some studied non-MDS malignancies (\n P<\/jats:italic>\n \u02c2 0.05). Receiver operating characteristics (ROC) analysis and area under the curve (AUC) suggested that the expression of\n TLR2, TLR4<\/jats:italic>\n , and\n IRAK4<\/jats:italic>\n (AUC = 0.702, AUC = 0.75, and AUC = 0.682, respectively) had acceptable diagnostic values to identify MDS from the other understudied leukemias.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion:<\/jats:title>\n \n Overall, the expression of\n TLR2, TLR4<\/jats:italic>\n , and\n IRAK4<\/jats:italic>\n could be potential biomarkers for discriminating MDS from some hematologic disorders.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.4103\/abr.abr_67_23","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T07:00:09Z","timestamp":1708930809000},"update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":4,"title":["Toll-Like Receptor 4, 2, and Interleukin 1 Receptor Associated Kinase4: Possible Diagnostic Biomarkers in Myelodysplastic Syndrome Patients"],"prefix":"10.4103","volume":"13","author":[{"given":"Parvin","family":"Khalilian","sequence":"first","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahid","family":"Eskandari","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran"},{"name":"Applied Physiology Research Center, Isfahan Cardiovascular Research Institute, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Jafar","family":"Sharifi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Soltani","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pardis","family":"Nematollahi","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Cancer Prevention Research Center, Seyyed Al-Shohada Hospital, Isfahan University of Medical Sciences, Isfahan, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2024,2]]},"reference":[{"key":"R1-20240830","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1002\/ajh.24253","article-title":"Myelodysplastic syndromes: Contemporary review and how we treat","volume":"91","author":"Gangat","year":"2016","journal-title":"Am J Hematol"},{"key":"R2-20240830","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1053\/j.seminhematol.2018.05.015","article-title":"The current approach to the diagnosis of myelodysplastic syndromes","volume":"56","author":"Weinberg","year":"2019","journal-title":"Semin Hematol"},{"key":"R3-20240830","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1182\/blood-2005-01-0040","article-title":"Difference in clinical features between Japanese and German patients with refractory anemia in myelodysplastic syndromes","volume":"106","author":"Matsuda","year":"2005","journal-title":"Blood"},{"issue":"S","key":"R4-20240830","doi-asserted-by":"crossref","first-page":"S75","DOI":"10.1016\/j.clml.2017.02.016","article-title":"Treatment choices: A quality of life comparison in acute myeloid leukemia and high-risk myelodysplastic syndrome","volume":"17","author":"Tinsley","year":"2017","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"R5-20240830","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/ajh.24930","article-title":"Myelodysplastic syndromes:2018 update on diagnosis, risk-stratification and management","volume":"93","author":"Montalban-Bravo","year":"2018","journal-title":"Am J Hematol"},{"key":"R6-20240830","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1159\/000489702","article-title":"Myelodysplastic syndrome updated","volume":"86","author":"Hasserjian","year":"2019","journal-title":"Pathobiology"},{"key":"R7-20240830","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1007\/s00018-015-1846-x","article-title":"The inflammatory microenvironment in MDS","volume":"72","author":"Yang","year":"2015","journal-title":"Cell Mol Life Sci"},{"key":"R8-20240830","doi-asserted-by":"crossref","first-page":"e20201544","DOI":"10.1084\/jem.20201544","article-title":"Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS","volume":"218","author":"Trowbridge","year":"2021","journal-title":"J Exp Med"},{"key":"R9-20240830","first-page":"1","article-title":"Immune dysregulation and recurring mutations in myelodysplastic syndromes pathogenesis","volume":"1326","author":"Matos","year":"2021","journal-title":"Adv Exp Med Biol"},{"key":"R10-20240830","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.3389\/fimmu.2020.01236","article-title":"Contribution of aberrant toll like receptor signaling to the pathogenesis of myelodysplastic syndromes","volume":"11","author":"Paracatu","year":"2020","journal-title":"Front Immunol"},{"key":"R11-20240830","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1007\/s11684-015-0412-0","article-title":"Toll-like receptor signaling in hematopoietic homeostasis and the pathogenesis of hematologic diseases","volume":"9","author":"Cannova","year":"2015","journal-title":"Front Med"},{"key":"R12-20240830","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1182\/blood-2018-03-784116","article-title":"Chronic immune response dysregulation in MDS pathogenesis","volume":"132","author":"Barreyro","year":"2018","journal-title":"Blood"},{"key":"R13-20240830","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1158\/1078-0432.CCR-06-2108","article-title":"Toll-like receptor-4 is up-regulated in hematopoietic progenitor cells and contributes to increased apoptosis in myelodysplastic syndromes","volume":"13","author":"Maratheftis","year":"2007","journal-title":"Clin Cancer Res"},{"key":"R14-20240830","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.critrevonc.2017.12.013","article-title":"Immune dysregulation in myelodysplastic syndrome: Clinical features, pathogenesis and therapeutic strategies","volume":"122","author":"Wang","year":"2018","journal-title":"Crit Rev Oncol Hematol"},{"key":"R15-20240830","doi-asserted-by":"crossref","first-page":"e71120","DOI":"10.1371\/journal.pone.0071120","article-title":"Overexpression of the toll-like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes","volume":"8","author":"Dimicoli","year":"2013","journal-title":"PLoS One"},{"key":"R16-20240830","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.blre.2019.04.004","article-title":"Flaming and fanning: The spectrum of inflammatory influences in myelodysplastic syndromes","volume":"36","author":"Banerjee","year":"2019","journal-title":"Blood Rev"},{"key":"R17-20240830","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1038\/leu.2013.180","article-title":"Toll-like receptor alterations in myelodysplastic syndrome","volume":"27","author":"Wei","year":"2013","journal-title":"Leukemia"},{"key":"R18-20240830","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nature14131","article-title":"Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells","volume":"520","author":"Walter","year":"2015","journal-title":"Nature"},{"key":"R19-20240830","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.cellsig.2015.02.025","article-title":"Interleukin-1 receptor associated kinase inhibitors: Potential therapeutic agents for inflammatory- and immune-related disorders","volume":"27","author":"Bahia","year":"2015","journal-title":"Cell Signal"},{"key":"R20-20240830","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1158\/0008-5472.CAN-17-2445","article-title":"IRAK1 augments cancer stemness and drug resistance via the AP-1\/AKR1B10 signaling cascade in hepatocellular carcinoma","volume":"78","author":"Cheng","year":"2018","journal-title":"Cancer Res"},{"key":"R21-20240830","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/s41556-019-0314-5","article-title":"U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies","volume":"21","author":"Smith","year":"2019","journal-title":"Nat Cell Biol"},{"key":"R22-20240830","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1182\/hematology.2022000350","article-title":"Targeting inflammation in lower-risk MDS","volume":"2022","author":"Gonzalez-Lugo","year":"2022","journal-title":"Hematology Am Soc Hematol Educ Program"},{"key":"R23-20240830","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1182\/blood-2016-03-643544","article-title":"The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia","volume":"127","author":"Arber","year":"2016","journal-title":"Blood"},{"key":"R24-20240830","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res"},{"key":"R25-20240830","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1007\/s11899-015-0270-5","article-title":"Myelodysplastic syndromes diagnosis: What is the role of molecular testing?","volume":"10","author":"Bejar","year":"2015","journal-title":"Curr Hematol Malig Rep"},{"key":"R26-20240830","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.yexcr.2015.12.008","article-title":"Apoptosis in human myelodysplastic syndrome CD34+cells is modulated by the upregulation of TLRs and histone H4 acetylation via a \u03b2-arrestin 1 dependent mechanism","volume":"340","author":"Zeng","year":"2016","journal-title":"Exp Cell Res"},{"key":"R27-20240830","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.3324\/haematol.2012.064642","article-title":"Impaired clearance of apoptotic cells leads to HMGB1 release in the bone marrow of patients with myelodysplastic syndromes and induces TLR4-mediated cytokine production","volume":"98","author":"Velegraki","year":"2013","journal-title":"Haematologica"},{"key":"R28-20240830","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/MOH.0000000000000693","article-title":"IRAK1 and IRAK4 as emerging therapeutic targets in hematologic malignancies","volume":"29","author":"Bennett","year":"2022","journal-title":"Curr Opin Hematol"},{"key":"R29-20240830","doi-asserted-by":"crossref","first-page":"724","DOI":"10.2174\/156802609789044407","article-title":"IRAK-4 inhibitors for inflammation","volume":"9","author":"Wang","year":"2009","journal-title":"Curr Top Med Chem"},{"key":"R30-20240830","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/s41375-019-0507-8","article-title":"Targeting IRAK4 disrupts inflammatory pathways and delays tumor development in chronic lymphocytic leukemia","volume":"34","author":"Gim\u00e9nez","year":"2020","journal-title":"Leukemia"},{"key":"R31-20240830","doi-asserted-by":"crossref","first-page":"4071","DOI":"10.1038\/sj.onc.1210187","article-title":"NF-kappaB inhibition sensitizes to starvation-induced cell death in high-risk myelodysplastic syndrome and acute myeloid leukemia","volume":"26","author":"Fabre","year":"2007","journal-title":"Oncogene"},{"key":"R32-20240830","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/s41375-018-0267-x","article-title":"Activation of NF-?B driven inflammatory programs in mesenchymal elements attenuates hematopoiesis in low-risk myelodysplastic syndromes","volume":"33","author":"Ping","year":"2019","journal-title":"Leukemia"},{"key":"R33-20240830","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.immuni.2005.02.009","article-title":"Stroma-mediated dysregulation of myelopoiesis in mice lacking I kappa B alpha","volume":"22","author":"Rupec","year":"2005","journal-title":"Immunity"},{"key":"R34-20240830","doi-asserted-by":"crossref","first-page":"e20200731","DOI":"10.1084\/jem.20200731","article-title":"TIRAP drives myelosuppression through an Ifn\u03b3-Hmgb1 axis that disrupts the endothelial niche in mice","volume":"219","author":"Gopal","year":"2022","journal-title":"J Exp Med"},{"key":"R35-20240830","doi-asserted-by":"crossref","first-page":"e78136","DOI":"10.7554\/eLife.78136","article-title":"Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations","volume":"11","author":"Choudhary","year":"2022","journal-title":"eLife"},{"key":"R36-20240830","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1182\/blood-2018-10-844654","article-title":"The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes","volume":"133","author":"Sallman","year":"2019","journal-title":"Blood"},{"key":"R37-20240830","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.1182\/bloodadvances.2020003475","article-title":"Oxidized mitochondrial DNA released after inflammasome activation is a disease biomarker for myelodysplastic syndromes","volume":"5","author":"Ward","year":"2021","journal-title":"Blood Adv"},{"key":"R38-20240830","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1038\/leu.2015.69","article-title":"Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes","volume":"29","author":"Ga\u00f1\u00e1n-G\u00f3mez","year":"2015","journal-title":"Leukemia"},{"key":"R39-20240830","doi-asserted-by":"crossref","first-page":"e393","DOI":"10.1016\/S2352-3026(18)30109-1","article-title":"Assessment of ASC specks as a putative biomarker of pyroptosis in myelodysplastic syndromes: An observational cohort study","volume":"5","author":"Basiorka","year":"2018","journal-title":"Lancet Haematol"},{"key":"R40-20240830","first-page":"786","article-title":"Expression profile of Toll-like receptors in human breast cancer","volume":"21","author":"Shi","year":"2020","journal-title":"Mol Med Rep"},{"key":"R41-20240830","doi-asserted-by":"crossref","first-page":"254","DOI":"10.3892\/ol.2021.12516","article-title":"Interleukin-1 receptor-associated kinase 4 as a potential biomarker: Overexpression predicts poor prognosis in patients with glioma","volume":"21","author":"Wang","year":"2021","journal-title":"Oncol Lett"},{"key":"R42-20240830","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.neulet.2014.11.020","article-title":"Toll-like receptor 4 and tumor necrosis factor-alpha as diagnostic biomarkers for diabetic peripheral neuropathy","volume":"585","author":"Zhu","year":"2015","journal-title":"Neurosci Lett"},{"key":"R43-20240830","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.exphem.2022.03.011","article-title":"Toll-like receptor and cytokine expression throughout the bone marrow differs between patients with low- and high-risk myelodysplastic syndromes","volume":"110","author":"Paracatu","year":"2022","journal-title":"Exp Hematol"}],"container-title":["Advanced Biomedical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.4103\/abr.abr_67_23","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T18:22:38Z","timestamp":1787768558000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/abr.abr_67_23"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2]]},"references-count":43,"URL":"https:\/\/doi.org\/10.4103\/abr.abr_67_23","relation":{},"ISSN":["2277-9175"],"issn-type":[{"value":"2277-9175","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2]]},"assertion":[{"value":"2023-02-21","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-10","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}