{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:03:44Z","timestamp":1776272624047,"version":"3.50.1"},"reference-count":64,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,22]],"date-time":"2024-09-22T00:00:00Z","timestamp":1726963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Internal Research Program in University Clinical Centre Maribor","award":["IRP-2019\/01-01"],"award-info":[{"award-number":["IRP-2019\/01-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Introduction: Advanced chronic lymphocytic leukemia (CLL) is accompanied by increased circulating regulatory T cells (Tregs) and increased susceptibility to severe infections, which were also shown to entail a striking induction of FOXP3 expression in Tregs. As homeostasis of the most suppressive CD45RA\u2212FOXP3high activated Treg (aTreg) subset differs, it is critical to analyse homeostatic signalling in Treg subsets. Materials and Methods: In this study, by using conventional and imaging flow cytometry, we monitored STAT5 signalling\/phosphorylation (pSTAT5) and investigated Treg subsets in relation to the Binet stage, the total tumor mass score (TTM) and the disease course during a follow-up of 37 patients with CLL. Results: The aTreg percentage was significantly increased among CD4+ T cells from patients with advanced disease and significantly correlated with the TTM. A subgroup of patients with higher aTreg percentages among CD4+FOXP3+ T cells at the start of therapy was characterised by more frequent episodes of severe infections during follow-up. Conclusions: The results suggesting that an aTreg fraction could represent a possible marker of a severe disease course with infectious complications. Augmented homeostatic STAT5 signalling could support aTreg expansion, as higher pSTAT5 levels were significantly correlated with an increased aTreg frequency among CD4+FOXP3+ T cells during the follow-up of patients on therapy, as well as following SARS-CoV-2 antigen-specific stimulation in vitro.<\/jats:p>","DOI":"10.3390\/cancers16183228","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T09:15:07Z","timestamp":1727082907000},"page":"3228","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Increased Frequency of Circulating Activated FOXP3+ Regulatory T Cell Subset in Patients with Chronic Lymphocytic Leukemia Is Associated with the Estimate of the Size of the Tumor Mass, STAT5 Signaling and Disease Course during Follow-Up of Patients on Therapy"],"prefix":"10.3390","volume":"16","author":[{"given":"Zlatko","family":"Ro\u0161kar","sequence":"first","affiliation":[{"name":"Department of Haematology, University Medical Centre Maribor, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mojca","family":"Dreisinger","sequence":"additional","affiliation":[{"name":"Department of Haematology, University Medical Centre Maribor, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evgenija","family":"Hom\u0161ak","sequence":"additional","affiliation":[{"name":"Department of Laboratory Diagnostics, University Medical Centre Maribor, 2000 Maribor, Slovenia"},{"name":"Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadej","family":"Av\u010din","sequence":"additional","affiliation":[{"name":"Department of Allergology, Rheumatology and Clinical Immunology, Children\u2019s Hospital, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"},{"name":"Department of Pediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2313-1559","authenticated-orcid":false,"given":"Sebastjan","family":"Bevc","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia"},{"name":"Department of Nephrology, University Medical Centre Maribor, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ale\u0161","family":"Goropev\u0161ek","sequence":"additional","affiliation":[{"name":"Department of Laboratory Diagnostics, University Medical Centre Maribor, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer statistics","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Dubois, N., Crompot, E., Meuleman, N., Bron, D., Lagneaux, L., and Stamatopoulos, B. (2020). Importance of Crosstalk between Chronic lymphocytic leukemia cells and the Stromal Microenvironment: Direct contact, soluble factors, and Extracellular vesicles. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.01422"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1038\/s41375-020-0959-x","article-title":"COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: A joint study by ERIC, the European Research Initiative on CLL, and CLL Campus","volume":"34","author":"Chatzikonstantinou","year":"2020","journal-title":"Leukemia"},{"key":"ref_4","unstructured":"Hospital, P., Alliance, C.C., York, N., Hospital, P., Hospital, B., and Cornell, W. (2021). Outcomes of COVID-19 in Patients with CLL: A Multicenter, International Experience."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.blre.2018.03.004","article-title":"Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: Linking mechanisms with infections","volume":"32","author":"Hilal","year":"2018","journal-title":"Blood Rev."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Arruga, F., Gyau, B.B., Iannello, A., Vitale, N., Vaisitti, T., and Deaglio, S. (2020). Immune Response Dysfunction in Chronic lymphocytic leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051825"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1159\/000514071","article-title":"Immune Dysfunction in Patients with Chronic Lymphocytic Leukemia and Challenges during COVID-19 Pandemic","volume":"144","author":"Langerbeins","year":"2021","journal-title":"Acta Haematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.blre.2018.04.007","article-title":"Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies","volume":"32","author":"Teh","year":"2018","journal-title":"Blood Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/s41408-021-00528-x","article-title":"Antibody responses after first and second COVID-19 vaccination in patients with chronic lymphocytic leukaemia","volume":"11","author":"Parry","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1111\/bjh.17743","article-title":"Serological SARS-CoV-2 antibody response, potential predictive markers and safety of BNT162b2 mRNA COVID-19 vaccine in haematological and oncological patients","volume":"195","author":"Benda","year":"2021","journal-title":"Br. J. Haematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1146\/annurev.immunol.18.1.423","article-title":"Regulatory T cells in autoimmmunity","volume":"18","author":"Shevach","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1111\/j.1600-065X.2011.01018.x","article-title":"Regulatory T cells and Foxp3","volume":"241","author":"Rudensky","year":"2011","journal-title":"Immunol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1146\/annurev.immunol.21.120601.141122","article-title":"Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses","volume":"22","author":"Sakaguchi","year":"2004","journal-title":"Annu. Rev. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.canlet.2020.07.022","article-title":"FoxP3+ T regulatory cells in cancer: Prognostic biomarkers and therapeutic targets","volume":"490","author":"Saleh","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.immuni.2009.03.019","article-title":"Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor","volume":"30","author":"Miyara","year":"2009","journal-title":"Immunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1038\/s41590-019-0429-7","article-title":"Connecting blood and intratumoral Treg cell activity in predicting future relapse in breast cancer","volume":"20","author":"Wang","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.leukres.2010.08.010","article-title":"Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease","volume":"35","author":"Laurenti","year":"2011","journal-title":"Leuk. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.leukres.2017.07.004","article-title":"Quantitative and qualitative analysis of regulatory T cells in B cell chronic lymphocytic leukemia","volume":"60","author":"Mpakou","year":"2017","journal-title":"Leuk. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1002\/ajh.23170","article-title":"A shorter time to the first treatment may be predicted by the absolute number of regulatory T-cells in patients with Rai stage 0 chronic lymphocytic leukemia","volume":"87","author":"Simeon","year":"2012","journal-title":"Am. J. Hematol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1002\/cncr.25752","article-title":"Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia","volume":"117","author":"Weiss","year":"2010","journal-title":"Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9273","DOI":"10.18632\/oncotarget.23949","article-title":"Single cell profiling of phospho-protein levels in chronic lymphocytic leukemia","volume":"9","author":"Myhrvold","year":"2018","journal-title":"Oncotarget"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Blix, E.S., Irish, J.M., Husebekk, A., Delabie, J., Forfang, L., Tierens, A.M., Myklebust, J.H., and Kolstad, A. (2012). Phospho-specific flow cytometry identifies aberrant signaling in indolent B-cell lymphoma. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-478"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/nri2580","article-title":"New insights into the regulation of T cells by gamma(c) family cytokines","volume":"9","author":"Rochman","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e23154","DOI":"10.4161\/jkst.23154","article-title":"Interleukin-2 and STAT5 in regulatory T cell development and function","volume":"2","author":"Mahmud","year":"2013","journal-title":"Jak-Stat"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.cyto.2014.05.021","article-title":"Comparative dose-responses of recombinant human IL-2 and IL-7 on STAT5 phosphorylation in CD4+FOXP3\u2212 cells versus regulatory T cells: A whole blood perspective","volume":"69","author":"Dupont","year":"2014","journal-title":"Cytokine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1182\/blood-2017-09-806398","article-title":"iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL","volume":"131","author":"Hallek","year":"2018","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/1097-0142(19810701)48:1<198::AID-CNCR2820480131>3.0.CO;2-V","article-title":"A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis","volume":"48","author":"Binet","year":"1981","journal-title":"Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1365-2141.1981.tb07243.x","article-title":"Total tumour mass score (TTM): A new parameter in chronic lymphocyte leukaemia","volume":"49","author":"Vitale","year":"1981","journal-title":"Br. J. Haematol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Trapecar, M., Goropev\u0161ek, A., Gorenjak, M., Gradisnik, L., and Rupnik, M.S. (2014). A Co-Culture Model of the Developing Small Intestine Offers New Insight in the Early Immunomodulation of Enterocytes and Macrophages by Lactobacillus spp. through STAT1 and NF-kB p65 Translocation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086297"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.jim.2006.01.018","article-title":"Quantitative measurement of nuclear translocation events using similarity analysis of multispectral cellular images obtained in flow","volume":"311","author":"George","year":"2006","journal-title":"J. Immunol. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.4049\/jimmunol.167.3.1245","article-title":"CD4+ CD25high regulatory cells in human peripheral blood","volume":"167","author":"Brown","year":"2001","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/nri2785","article-title":"FOXP3+ regulatory T cells in the human immune system","volume":"10","author":"Sakaguchi","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ro\u0161kar, Z., Dreisinger, M., Ti\u010d, P., Hom\u0161ak, E., Bevc, S., and Goropev\u0161ek, A. (2023). New Flow Cytometric Methods for Monitoring STAT5 Signaling Reveal Responses to SARS-CoV-2 Antigen-Specific Stimulation in FOXP3+ Regulatory T Cells also in Patients with Advanced Chronic Lymphocytic Leukemia. Biosensors, 13.","DOI":"10.3390\/bios13050539"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/cyto.a.10072","article-title":"Intracellular phospho-protein staining techniques for flow cytometry: Monitoring single cell signaling events","volume":"55","author":"Krutzik","year":"2003","journal-title":"Cytom. Part A J. Int. Soc. Anal. Cytol."},{"key":"ref_35","first-page":"e2111315118.36","article-title":"Profound Treg perturbations correlate with COVID-19 severity","volume":"118","author":"Leon","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/nm.2130","article-title":"A CD8+ T cell transcription signature predicts prognosis in autoimmune disease","volume":"16","author":"McKinney","year":"2010","journal-title":"Nat. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1189\/jlb.5A0416-194R","article-title":"STAT5 phosphorylation in CD4 T cells from patients with SLE is related to changes in their subsets and follow-up disease severity","volume":"101","author":"Gorenjak","year":"2017","journal-title":"J. Leukoc. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.4049\/jimmunol.133.4.1710","article-title":"Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67","volume":"133","author":"Gerdes","year":"1984","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Goral, A., Firczuk, M., Fidyt, K., Sledz, M., Simoncello, F., Siudakowska, K., Pagano, G., Moussay, E., Paggetti, J., and Nowakowska, P. (2022). A Specific CD44lo CD25lo Subpopulation of Regulatory T Cells Inhibits Anti-Leukemic Immune Response and Promotes the Progression in a Mouse Model of Chronic Lymphocytic Leukemia. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.781364"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1111\/j.1365-2249.2011.04466.x","article-title":"Chronic lymphocytic leukaemia cells drive the global CD4+ T cell repertoire towards a regulatory phenotype and leads to the accumulation of CD4+ forkhead box P3+ T cells","volume":"166","author":"Piper","year":"2011","journal-title":"Clin. Exp. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"778","DOI":"10.3109\/10428194.2012.730614","article-title":"Flow cytometric immunophenotyping of regulatory T cells in chronic lymphocytic leukemia: Comparative assessment of various markers and use of novel antibody panel with CD127 as alternative to transcription factor FoxP3","volume":"54","author":"Dasgupta","year":"2013","journal-title":"Leuk. Lymphoma"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1126\/science.1160062","article-title":"CTLA-4 control over Foxp3+ regulatory T cell function","volume":"322","author":"Wing","year":"2008","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6250","DOI":"10.1073\/pnas.0901166106","article-title":"E(mu)-TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction","volume":"106","author":"Gorgun","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/leu.2015.174","article-title":"The BAFF receptor TACI controls IL-10 production by regulatory b cells and CLL b cells","volume":"30","author":"Vincent","year":"2016","journal-title":"Leukemia"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Allegra, A., Musolino, C., Tonacci, A., Pioggia, G., Casciaro, M., and Gangemi, S. (2020). Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role. Cancers, 12.","DOI":"10.3390\/cancers12020524"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.2217\/fon.14.298","article-title":"The skewed balance between Tregs and Th17 in chronic lymphocytic leukemia","volume":"11","author":"Yousefi","year":"2015","journal-title":"Future Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/modpathol.2011.164","article-title":"Phenotypic complexity of T regulatory subsets in patients with B-chronic lymphocytic leukemia","volume":"25","author":"Biancotto","year":"2012","journal-title":"Mod. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Gonder, S., Fernandez Botana, I., Wierz, M., Pagano, G., Gargiulo, E., Cosma, A., Moussay, E., Paggetti, J., and Largeot, A. (2020). Method for the Analysis of the Tumor Microenvironment by Mass Cytometry: Application to Chronic Lymphocytic Leukemia. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.578176"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.immuni.2021.03.020","article-title":"A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance","volume":"54","author":"Dikiy","year":"2021","journal-title":"Immunity"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"332","DOI":"10.4049\/jimmunol.0900691","article-title":"The initial phase of an immune response functions to activate regulatory T cells","volume":"183","author":"Dooms","year":"2009","journal-title":"J. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Boer, M.C., Joosten, S.A., and Ottenhoff, T.H. (2015). Regulatory T-Cells at the Interface between Human Host and Pathogens in Infectious Diseases and Vaccination. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00217"},{"key":"ref_52","first-page":"677","article-title":"Characterization of regulatory T cells in patients with b-cell chronic lymphocytic leukemia","volume":"20","author":"Giannopoulos","year":"2008","journal-title":"Oncol. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/s41577-023-00893-7","article-title":"The role of transcription factors in shaping regulatory T cell identity","volume":"23","author":"Kazemian","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Chi, V.L.D., Garaud, S., De Silva, P., Thibaud, V., Stamatopoulos, B., Berehad, M., Gu-Trantien, C., Krayem, M., Duvillier, H., and Lodewyckx, J.N. (2019). Age-related changes in the BACH2 and PRDM1 genes in lymphocytes from healthy donors and chronic lymphocytic leukemia patients. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5276-2"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e20190711","DOI":"10.1084\/jem.20190711","article-title":"BACH2 drives quiescence and maintenance of resting Treg cells to promote homeostasis and cancer immunosuppression","volume":"217","author":"Grant","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Ciardullo, C., Szoltysek, K., Zhou, P., Pietrowska, M., Marczak, L., Willmore, E., Enshaei, A., Walaszczyk, A., Ho, J.Y., and Rand, V. (2021). Low BACH2 Expression Predicts Adverse Outcome in Chronic Lymphocytic Leukaemia. Cancers, 14.","DOI":"10.3390\/cancers14010023"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Gauthier, M., Durrieu, F., Martin, E., Peres, M., Vergez, F., Filleron, T., Ob\u00e9ric, L., Bijou, F., Quillet, M.A., and Ysebaert, L. (2019). Prognostic role of CD4 T-cell depletion after frontline fludarabine, cyclophosphamide and rituximab in chronic lymphocytic leukaemia. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5971-z"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6956","DOI":"10.1002\/cam4.5492","article-title":"A comprehensive assessment of lymphocyte subsets, their prognostic significance, and changes after first-line therapy administration in patients with chronic lymphocytic leukemia","volume":"12","author":"Belada","year":"2023","journal-title":"Cancer Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1182\/blood.2023020554","article-title":"Ibrutinib-based therapy reinvigorates CD8+ T cells compared to chemoimmunotherapy: Immune monitoring from the E1912 trial","volume":"143","author":"Papazoglou","year":"2024","journal-title":"Blood"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.4049\/jimmunol.164.5.2533","article-title":"The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2, and bcl-x genes through the trans-activation domain of Stat5","volume":"164","author":"Lord","year":"2000","journal-title":"J. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12943-022-01516-w","article-title":"BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion","volume":"21","author":"Liu","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_62","first-page":"1292404","article-title":"CD4+CD25highCD127low\/-FoxP3+ Regulatory T Cell Subpopulations in the Bone Marrow and Peripheral Blood of Children with ALL: Brief Report","volume":"2018","author":"Trzonkowski","year":"2018","journal-title":"J. Immunol. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1080\/10428194.2017.1330475","article-title":"Regulatory T-cells drive immune dysfunction in CLL","volume":"59","author":"Lad","year":"2018","journal-title":"Leuk. Lymphoma"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"423","DOI":"10.3324\/haematol.11897","article-title":"CD4+CD25+FOXP3+ T regulatory cells reconstitute and accumulate in the bone marrow of patients with multiple myeloma following allogeneic stem cell transplantation","volume":"93","author":"Atanackovic","year":"2008","journal-title":"Haematologica"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/18\/3228\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:02:12Z","timestamp":1760112132000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/18\/3228"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,22]]},"references-count":64,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["cancers16183228"],"URL":"https:\/\/doi.org\/10.3390\/cancers16183228","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,22]]}}}