{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T20:47:29Z","timestamp":1779914849968,"version":"3.53.1"},"reference-count":42,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,5]],"date-time":"2021-06-05T00:00:00Z","timestamp":1622851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010621","name":"Uniwersytet Medyczny w Lublinie","doi-asserted-by":"publisher","award":["Ds 458"],"award-info":[{"award-number":["Ds 458"]}],"id":[{"id":"10.13039\/501100010621","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Tie2-expressing monocytes (TEMs) are associated with tumor progression and metastasis. This unique subset of monocytes has been identified as a potential prognostic marker in several solid tumors. However, TEMs remain poorly characterized in hematological cancers, including chronic lymphocytic leukemia (CLL). This study analyzed, for the first time, the clinical significance of TEM population in CLL patients. Flow cytometry analysis of TEMs (defined as CD14+CD16+Tie2+ cells) was performed at the time of diagnosis on peripheral blood mononuclear cells from 104 untreated CLL patients. Our results revealed an expansion of circulating TEM in CLL patients. These monocytes express high levels of VEGF and suppressive IL-10. A high percentage of TEM was associated closely with unfavorable prognostic markers (ZAP-70, CD38, 17p and 11q deletion, and IGHV mutational status). Moreover, increased percentages of circulating TEMs were significantly higher in patients not responding to the first-line therapy as compared to responding patients, suggesting its potential predictive value. High TEM percentage was also correlated with shorter overall survival (OS) and shorter time to treatment (TTT). Importantly, based on multivariate Cox regression analysis, TEM percentage was an independent predictor for TTT. Thus, we can suggest the adverse role of TEMs in CLL.<\/jats:p>","DOI":"10.3390\/cancers13112817","type":"journal-article","created":{"date-parts":[[2021,6,6]],"date-time":"2021-06-06T23:59:55Z","timestamp":1623023995000},"page":"2817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Prognostic Value of Tie2-Expressing Monocytes in Chronic Lymphocytic Leukemia Patients"],"prefix":"10.3390","volume":"13","author":[{"given":"Justyna","family":"Wo\u015b","sequence":"first","affiliation":[{"name":"Chair and Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylwia","family":"Chocholska","sequence":"additional","affiliation":[{"name":"Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0930-5874","authenticated-orcid":false,"given":"Wioleta","family":"Kowalska","sequence":"additional","affiliation":[{"name":"Chair and Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waldemar","family":"Tomczak","sequence":"additional","affiliation":[{"name":"Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3764-7452","authenticated-orcid":false,"given":"Agata","family":"Szyma\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Clinical Transplantology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Karczmarczyk","sequence":"additional","affiliation":[{"name":"Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Szuster-Ciesielska","sequence":"additional","affiliation":[{"name":"Department of Virology and Immunology, Institute of Biological Sciences, Maria Curie-Sk\u0142odowska University, 20-033 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0854-7882","authenticated-orcid":false,"given":"Agnieszka","family":"Wojciechowska","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Wroclaw University of Science and Technology, 50-370 Wroc\u0142aw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2340-9442","authenticated-orcid":false,"given":"Agnieszka","family":"Bojarska-Junak","sequence":"additional","affiliation":[{"name":"Chair and Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"514","DOI":"10.3389\/fimmu.2014.00514","article-title":"From Monocytes to M1\/M2 Macrophages: Phenotypical vs. Functional Differentiation","volume":"5","author":"Italiani","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e74","DOI":"10.1182\/blood-2010-02-258558","article-title":"Nomenclature of monocytes and dendritic cells in blood","volume":"116","author":"Ancuta","year":"2010","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ccr.2005.08.002","article-title":"Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors","volume":"8","author":"Venneri","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5276","DOI":"10.1182\/blood-2006-10-053504","article-title":"Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer","volume":"109","author":"Venneri","year":"2007","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7405","DOI":"10.4049\/jimmunol.178.11.7405","article-title":"Expression of Tie-2 by Human Monocytes and Their Responses to Angiopoietin-2","volume":"178","author":"Murdoch","year":"2007","journal-title":"J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.it.2007.09.004","article-title":"Tie2-expressing monocytes: Regulation of tumor angiogenesis and therapeutic implications","volume":"28","author":"Murdoch","year":"2007","journal-title":"Trends Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5270","DOI":"10.1158\/0008-5472.CAN-10-0012","article-title":"Angiopoietin-2 Regulates Gene Expression in TIE2-Expressing Monocytes and Augments Their Inherent Proangiogenic Functions","volume":"70","author":"Coffelt","year":"2010","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1073882","DOI":"10.1080\/2162402X.2015.1073882","article-title":"TIE-2-expressing monocytes are lymphangiogenic and associate specifically with lymphatics of human breast cancer","volume":"5","author":"Bron","year":"2016","journal-title":"OncoImmunology"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lekas, M., Lekas, P., Mei, S., Deng, Y., Dumont, D.J., and Stewart, D.J. (2012). Tie2-Dependent Neovascularization of the Ischemic Hindlimb Is Mediated by Angiopoietin-2. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0043568"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4183","DOI":"10.4049\/jimmunol.1002802","article-title":"Angiopoietin 2 Stimulates TIE2-Expressing Monocytes To Suppress T Cell Activation and To Promote Regulatory T Cell Expansion","volume":"186","author":"Coffelt","year":"2011","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"He, Y.-F., Wang, C.-Q., Yu, Y., Qian, J., Song, K., Sun, Q.-M., and Zhou, J. (2015). Tie2-Expressing Monocytes Are Associated with Identification and Prognoses of Hepatitis B Virus Related Hepatocellular Carcinoma after Resection. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0143657"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.leukres.2009.06.023","article-title":"Increased angiogenesis induced by chronic lymphocytic leukemia B cells is mediated by leukemia-derived Ang2 and VEGF","volume":"34","author":"Maffei","year":"2010","journal-title":"Leuk. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8429","DOI":"10.1158\/0008-5472.CAN-07-1684","article-title":"Tie2-Expressing Monocytes and Tumor Angiogenesis: Regulation by Hypoxia and Angiopoietin-2: Figure 1","volume":"67","author":"Lewis","year":"2007","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.3324\/haematol.2012.073080","article-title":"The monocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation","volume":"98","author":"Maffei","year":"2013","journal-title":"Haematologica"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1182\/blood.V96.8.2655","article-title":"Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1","volume":"96","author":"Burger","year":"2000","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4223","DOI":"10.1182\/blood-2010-05-284505","article-title":"Soluble CD14 is a novel monocyte-derived survival factor for chronic lymphocytic leukemia cells, which is induced by CLL cells in vitro and present at abnormally high levels in vivo","volume":"116","author":"Seiffert","year":"2010","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/ajh.24376","article-title":"Relationship of blood monocytes with chronic lymphocytic leukemia aggressiveness and outcomes: A multi-institutional study","volume":"91","author":"Friedman","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5446","DOI":"10.1182\/blood-2007-06-093906","article-title":"Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: A report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute\u2013Working Group 1996 guidelines","volume":"111","author":"Hallek","year":"2008","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1182\/blood.V46.2.219.219","article-title":"Clinical staging of chronic lymphocytic leu-kemia","volume":"46","author":"Rai","year":"1975","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zarobkiewicz, M., Kowalska, W., Chocholska, S., Tomczak, W., Szyma\u0144ska, A., Morawska, I., Wojciechowska, A., and Bojarska-Junak, A. (2020). High M-MDSC Percentage as a Negative Prognostic Factor in Chronic Lymphocytic Leukaemia. Cancers, 12.","DOI":"10.3390\/cancers12092614"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1093\/annonc\/mdj120","article-title":"The clinical significance of ZAP-70 and CD38 expression in B-cell chronic lymphocytic leukaemia","volume":"17","author":"Hus","year":"2006","journal-title":"Ann. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.leukres.2013.12.015","article-title":"CD1d expression is higher in chronic lymphocytic leukemia patients with unfavorable prognosis","volume":"38","author":"Hus","year":"2014","journal-title":"Leuk. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.bbamcr.2015.07.009","article-title":"Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment","volume":"1863","author":"Hacken","year":"2016","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.3324\/haematol.2016.142679","article-title":"Chronic lymphocytic leukemia cells are active participants in microenvironmental cross-talk","volume":"102","author":"Eldering","year":"2017","journal-title":"Haematologica"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Petty, A.J., and Yang, Y. (2019). Tumor-Associated Macrophages in Hematologic Malignancies: New Insights and Targeted Therapies. Cells, 8.","DOI":"10.3390\/cells8121526"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1002\/ijc.33381","article-title":"Tie2-expressing monocytes as a novel angiogenesis-related cellular biomarker for non-small cell lung cancer","volume":"148","author":"Xue","year":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.bbcan.2009.04.001","article-title":"Tie2-expressing monocytes (TEMs): Novel targets and vehicles of anticancer therapy?","volume":"1796","author":"Naldini","year":"2009","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e1303585","DOI":"10.1080\/2162402X.2017.1303585","article-title":"TIE-2 expressing monocytes in human cancers","volume":"6","author":"Turrini","year":"2017","journal-title":"OncoImmunology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1634\/stemcells.2006-0700","article-title":"Expression of Tie-2 and Other Receptors for Endothelial Growth Factors in Acute Myeloid Leukemias Is Associated with Monocytic Features of Leukemic Blasts","volume":"25","author":"Riccioni","year":"2007","journal-title":"STEM CELLS"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1002\/hep.25965","article-title":"TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis","volume":"57","author":"Matsubara","year":"2013","journal-title":"Hepatology"},{"key":"ref_31","first-page":"6","article-title":"Angiopoietin-2\/Tie2 Signaling in the Microenvironment of Chronic Lymphocytic Leukemia (CLL)","volume":"3","author":"Gehrke","year":"2014","journal-title":"Res. Cancer Tumor"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3181","DOI":"10.1182\/blood.V96.9.3181","article-title":"In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells","volume":"96","author":"Chen","year":"2000","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3344","DOI":"10.1182\/blood-2002-01-0084","article-title":"Prognostic value of enhanced bone marrow angiogenesis in early B-cell chronic lymphocytic leukemia","volume":"100","author":"Molica","year":"2002","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s12307-016-0180-7","article-title":"Angiopoietins Modulate Survival, Migration, and the Components of the Ang-Tie2 Pathway of Chronic Lymphocytic Leukaemia (CLL) Cells In Vitro","volume":"9","author":"Palma","year":"2016","journal-title":"Cancer Microenviron."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1053\/j.seminoncol.2006.01.008","article-title":"The Clinical and Biologic Importance of Neovascularization and Angiogenic Signaling Pathways in Chronic Lymphocytic Leukemia","volume":"33","author":"Shanafelt","year":"2006","journal-title":"Semin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.critrevonc.2014.10.007","article-title":"Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand?","volume":"93","author":"Palma","year":"2015","journal-title":"Crit. Rev. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1002\/cncr.22086","article-title":"Role of angiogenesis in chronic lymphocytic leukemia","volume":"107","author":"Letilovic","year":"2006","journal-title":"Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1182\/blood-2009-11-252494","article-title":"Angiopoietin-2 plasma dosage predicts time to first treatment and overall survival in chronic lymphocytic leukemia","volume":"116","author":"Maffei","year":"2010","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.leukres.2007.09.002","article-title":"Increased expression of angiopoietin-2 characterizes early B-cell chronic lymphocytic leukemia with poor prognosis","volume":"32","author":"Martinelli","year":"2008","journal-title":"Leuk. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/nrc2894","article-title":"Targeting the ANGPT\u2013TIE2 pathway in malignancy","volume":"10","author":"Huang","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.3109\/10428194.2014.986479","article-title":"Regulatory T-cell and T-helper 17 balance in chronic lymphocytic leukemia progression and autoimmune cytopenias","volume":"56","author":"Lad","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1016\/j.celrep.2016.01.042","article-title":"Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression","volume":"14","author":"Galletti","year":"2016","journal-title":"Cell Rep."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/11\/2817\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:11:10Z","timestamp":1760163070000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/11\/2817"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,5]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["cancers13112817"],"URL":"https:\/\/doi.org\/10.3390\/cancers13112817","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,5]]}}}