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Here, we review in vitro and in vivo model systems that mimic CLL\u2013T-cell interactions, since these are critical for CLL-cell division and resistance to some types of therapy (such as DNA-damaging drugs or BH3-mimetic venetoclax). We discuss approaches for direct CLL-cell co-culture with autologous T cells, models utilizing supportive cell lines engineered to express T-cell factors (such as CD40L) or stimulating CLL cells with combinations of recombinant factors (CD40L, interleukins IL4 or IL21, INF\u03b3) and additional B-cell receptor (BCR) activation with anti-IgM antibody. We also summarize strategies for CLL co-transplantation with autologous T cells into immunodeficient mice (NOD\/SCID, NSG, NOG) to generate patient-derived xenografts (PDX) and the role of T cells in transgenic CLL mouse models based on TCL1 overexpression (E\u00b5-TCL1). We further discuss how these in vitro and in vivo models could be used to test drugs to uncover the effects of targeted therapies (such as inhibitors of BTK, PI3K, SYK, AKT, MEK, CDKs, BCL2, and proteasome) or chemotherapy (fludarabine and bendamustine) on CLL\u2013T-cell interactions and CLL proliferation.<\/jats:p>","DOI":"10.3390\/cancers14133087","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T21:25:00Z","timestamp":1656019500000},"page":"3087","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["In Vitro and In Vivo Models of CLL\u2013T Cell Interactions: Implications for Drug Testing"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7185-6119","authenticated-orcid":false,"given":"Eva","family":"Hoferkova","sequence":"first","affiliation":[{"name":"Molecular Medicine, CEITEC Masaryk University, 62500 Brno, Czech Republic"},{"name":"Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic"},{"name":"Faculty of Science, Masaryk University, 61137 Brno, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sona","family":"Kadakova","sequence":"additional","affiliation":[{"name":"Molecular Medicine, CEITEC Masaryk University, 62500 Brno, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Mraz","sequence":"additional","affiliation":[{"name":"Molecular Medicine, CEITEC Masaryk University, 62500 Brno, Czech Republic"},{"name":"Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1182\/blood-2006-05-021683","article-title":"Differential Noxa\/Mcl-1 Balance in Peripheral versus Lymph Node Chronic Lymphocytic Leukemia Cells Correlates with Survival Capacity","volume":"109","author":"Smit","year":"2007","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1038\/leu.2017.11","article-title":"Direct In Vivo Evidence for Increased Proliferation of CLL Cells in Lymph Nodes Compared to Bone Marrow and Peripheral Blood","volume":"31","author":"Herndon","year":"2017","journal-title":"Leukemia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1182\/blood-2010-05-284984","article-title":"The Lymph Node Microenvironment Promotes B-Cell Receptor Signaling, NF-\u039aB Activation, and Tumor Proliferation in Chronic Lymphocytic Leukemia","volume":"117","author":"Herishanu","year":"2011","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1038\/s41375-018-0211-0","article-title":"Rituximab Primarily Targets an Intra-Clonal BCR Signaling Proficient CLL Subpopulation Characterized by High CD20 Levels","volume":"32","author":"Pavlasova","year":"2018","journal-title":"Leukemia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/ejh.12427","article-title":"B-Cell Receptor Signalling and Its Crosstalk with Other Pathways in Normal and Malignant Cells","volume":"94","author":"Seda","year":"2015","journal-title":"Eur. J. Haematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.3389\/fonc.2020.592205","article-title":"Proliferative Signals in Chronic Lymphocytic Leukemia; What Are We Missing?","volume":"10","author":"Haselager","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"612244","DOI":"10.3389\/fimmu.2020.612244","article-title":"T Cells in Chronic Lymphocytic Leukemia: A Two-Edged Sword","volume":"11","author":"Vlachonikola","year":"2021","journal-title":"Front. 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Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1111\/bjh.12401","article-title":"Enhancement of CD154\/IL4 Proliferation by the T Follicular Helper (Tfh) Cytokine, IL21 and Increased Numbers of Circulating Cells Resembling Tfh Cells in Chronic Lymphocytic Leukaemia","volume":"162","author":"Ahearne","year":"2013","journal-title":"Br. J. Haematol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/leu.2011.12","article-title":"IGHV Unmutated CLL B Cells Are More Prone to Spontaneous Apoptosis and Subject to Environmental Prosurvival Signals than Mutated CLL B Cells","volume":"25","author":"Coscia","year":"2011","journal-title":"Leukemia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1182\/blood.V91.8.2689.2689_2689_2697","article-title":"Chronic Lymphocytic Leukemia B Cells Can Express CD40 Ligand and Demonstrate T-Cell Type Costimulatory Capacity","volume":"91","author":"Schattner","year":"1998","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.3109\/10428194.2010.503820","article-title":"Prognostic Significance of CD8 and CD4 T Cells in Chronic Lymphocytic Leukemia","volume":"51","author":"Contesti","year":"2010","journal-title":"Leuk. Lymphoma"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1172\/JCI89756","article-title":"Ibrutinib Treatment Improves T Cell Number and Function in CLL Patients","volume":"127","author":"Long","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1186\/s12967-021-03136-2","article-title":"Ibrutinib Protects T Cells in Patients with CLL from Proliferation-Induced Senescence","volume":"19","author":"Davis","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1172\/JCI24176","article-title":"Chronic Lymphocytic Leukemia Cells Induce Changes in Gene Expression of CD4 and CD8 T Cells","volume":"115","author":"Holderried","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1182\/blood.V74.2.786.786","article-title":"T-Cell Activation and Subset Patterns Are Altered in B-CLL and Correlate with the Stage of the Disease","volume":"74","author":"Carlsson","year":"1989","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1038\/leu.2016.362","article-title":"Restrictions in the T-Cell Repertoire of Chronic Lymphocytic Leukemia: High-Throughput Immunoprofiling Supports Selection by Shared Antigenic Elements","volume":"31","author":"Vardi","year":"2017","journal-title":"Leukemia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1182\/blood-2012-09-457531","article-title":"T Cells from CLL Patients Exhibit Features of T-Cell Exhaustion but Retain Capacity for Cytokine Production","volume":"121","author":"Riches","year":"2013","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1046\/j.1365-2141.1999.01642.x","article-title":"Bryostatin and CD40-Ligand Enhance Apoptosis Resistance and Induce Expression of Cell Survival Genes in B-Cell Chronic Lymphocytic Leukaemia","volume":"106","author":"Kitada","year":"1999","journal-title":"Br. J. Haematol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.celrep.2013.07.011","article-title":"Chronic Lymphocytic Leukemia Cells Are Activated and Proliferate in Response to Specific T Helper Cells","volume":"4","author":"Os","year":"2013","journal-title":"Cell Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1182\/blood-2005-02-0695","article-title":"Inhibitors of XIAP Sensitize CD40-Activated Chronic Lymphocytic Leukemia Cells to CD95-Mediated Apoptosis","volume":"106","author":"Kater","year":"2005","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3450","DOI":"10.1182\/blood-2006-04-017749","article-title":"CD154 Induces P73 to Overcome the Resistance to Apoptosis of Chronic Lymphocytic Leukemia Cells Lacking Functional P53","volume":"108","author":"Dicker","year":"2006","journal-title":"Blood"},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1182\/blood-2008-07-170415","article-title":"High-Level Expression of the T-Cell Chemokines CCL3 and CCL4 by Chronic Lymphocytic Leukemia B Cells in Nurselike Cell Cocultures and after BCR Stimulation","volume":"113","author":"Burger","year":"2009","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"563","DOI":"10.3109\/10428194.2015.1068308","article-title":"CCL3 Chemokine Expression by Chronic Lymphocytic Leukemia Cells Orchestrates the Composition of the Microenvironment in Lymph Node Infiltrates","volume":"57","author":"Hartmann","year":"2016","journal-title":"Leuk. Lymphoma"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1111\/bjh.15918","article-title":"Chronic Lymphocytic Leukaemia: The Role of T Cells in a B Cell Disease","volume":"186","author":"Man","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/s41375-022-01519-y","article-title":"Activation and Expansion of T-Follicular Helper Cells in Chronic Lymphocytic Leukemia Nurselike Cell Co-Cultures","volume":"36","author":"Vaca","year":"2022","journal-title":"Leukemia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.3109\/10428194.2012.672735","article-title":"CCL2 and CXCL2 Enhance Survival of Primary Chronic Lymphocytic Leukemia Cells in Vitro","volume":"53","author":"Burgess","year":"2012","journal-title":"Leuk. Lymphoma"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.2119\/molmed.2011.00360","article-title":"Intraclonal Complexity in Chronic Lymphocytic Leukemia: Fractions Enriched in Recently Born\/Divided and Older\/Quiescent Cells","volume":"17","author":"Calissano","year":"2011","journal-title":"Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1182\/blood.2020008101","article-title":"FoxO1-GAB1 Axis Regulates Homing Capacity and Tonic AKT Activity in Chronic Lymphocytic Leukemia","volume":"138","author":"Seda","year":"2021","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1182\/blood.2020005627","article-title":"MiR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: An Axis Affected by BCR Inhibitors","volume":"137","author":"Sharma","year":"2021","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7632","DOI":"10.18632\/oncotarget.2939","article-title":"Co-Culture of Primary CLL Cells with Bone Marrow Mesenchymal Cells, CD40 Ligand and CpG ODN Promotes Proliferation of Chemoresistant CLL Cells Phenotypically Comparable to Those Proliferating In Vivo","volume":"6","author":"Purroy","year":"2014","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1006\/cimm.1998.1360","article-title":"Direct Cellular Interaction with Activated CD4(+) T Cells Overcomes Hyporesponsiveness of B-Cell Chronic Lymphocytic Leukemia In Vitro","volume":"189","author":"Tretter","year":"1998","journal-title":"Cell Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5173","DOI":"10.1182\/blood-2007-08-108605","article-title":"CD38 Expression in Chronic Lymphocytic Leukemia Is Regulated by the Tumor Microenvironment","volume":"111","author":"Patten","year":"2008","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1080\/1042819031000111026","article-title":"Effects of Preactivated Autologous T Lymphocytes on CD80, CD86 and CD95 Expression by Chronic Lymphocytic Leukemia B Cells","volume":"44","author":"Romano","year":"2003","journal-title":"Leuk. Lymphoma"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1182\/blood-2012-11-467670","article-title":"IL-21 and CD40L Signals from Autologous T Cells Can Induce Antigen-Independent Proliferation of CLL Cells","volume":"122","author":"Pascutti","year":"2013","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Ghia, P., Circosta, P., Scielzo, C., Vallario, A., Camporeale, A., Granziero, L., and Caligaris-Cappio, F. (2005). Differential Effects on CLL Cell Survival Exerted by Different Microenvironmental Elements. Chronic Lymphocytic Leukemia, Springer. Current Topics in Microbiology and Immunology.","DOI":"10.1007\/3-540-29933-5_8"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1182\/blood.V128.22.350.350","article-title":"In Vitro Co-Culture of CLL-B Cells Reveals Long-Term Survival, Proliferation, and Maintenance of Telomere Length","volume":"128","author":"Jones","year":"2016","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wiesner, M., Zentz, C., Mayr, C., Wimmer, R., Hammerschmidt, W., Zeidler, R., and Moosmann, A. (2008). Conditional Immortalization of Human B Cells by CD40 Ligation. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001464"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1111\/j.1365-2141.2007.06717.x","article-title":"CD154 Induces a Switch in Pro-Survival Bcl-2 Family Members in Chronic Lymphocytic Leukaemia","volume":"138","author":"Willimott","year":"2007","journal-title":"Br. J. Haematol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1073\/pnas.85.2.564","article-title":"Stimulation of B-Cell Proliferation by Membrane-Associated Molecules from Activated T Cells","volume":"85","author":"Brian","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41598-018-36853-8","article-title":"BCR-Associated Factors Driving Chronic Lymphocytic Leukemia Cells Proliferation Ex Vivo","volume":"9","author":"Schleiss","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_45","first-page":"1373","article-title":"Generation of Human CD40-Activated B Cells","volume":"32","author":"Liebig","year":"2009","journal-title":"J. Vis. Exp."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18484","DOI":"10.18632\/oncotarget.3941","article-title":"Factors Involved in CLL Pathogenesis and Cell Survival Are Disrupted by Differentiation of CLL B-Cells into Antibody-Secreting Cells","volume":"6","author":"Ghamlouch","year":"2015","journal-title":"Oncotarget"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0145-2126(03)00028-6","article-title":"Influence of CD40 Ligation on Survival and Apoptosis of B-CLL Cells In Vitro","volume":"27","author":"Grdisa","year":"2003","journal-title":"Leuk. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4002","DOI":"10.1182\/blood-2004-02-0494","article-title":"Differential Regulation of Gene Expression Following CD40 Activation of Leukemic Compared to Healthy B Cells","volume":"104","author":"Gricks","year":"2004","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1038\/leu.2011.149","article-title":"The Functional in Vitro Response to CD40 Ligation Reflects a Different Clinical Outcome in Patients with Chronic Lymphocytic Leukemia","volume":"25","author":"Scielzo","year":"2011","journal-title":"Leukemia"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0145-2126(98)00005-8","article-title":"Release of Clonal Block in B Cell Chronic Lymphocytic Leukaemia by Engagement of Co-Operative Epitopes on CD40","volume":"22","author":"Jacob","year":"1998","journal-title":"Leuk. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00005-010-0108-8","article-title":"Tuning of CD40-CD154 Interactions in Human B-Lymphocyte Activation: A Broad Array of in Vitro Models for a Complex In Vivo Situation","volume":"59","author":"Nadeau","year":"2011","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1182\/blood.V97.9.2777","article-title":"Survivin Is Expressed on CD40 Stimulation and Interfaces Proliferation and Apoptosis in B-Cell Chronic Lymphocytic Leukemia","volume":"97","author":"Granziero","year":"2001","journal-title":"Blood"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1111\/j.1365-2567.2005.02244.x","article-title":"Differential Responses of Human B-Lymphocyte Subpopulations to Graded Levels of CD40-CD154 Interaction","volume":"116","author":"Racine","year":"2005","journal-title":"Immunology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1084\/jem.176.5.1319","article-title":"Interleukin 4 Protects Chronic Lymphocytic Leukemic B Cells from Death by Apoptosis and Upregulates Bcl-2 Expression","volume":"176","author":"Dancescu","year":"1992","journal-title":"J. Exp. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1182\/blood-2015-11-682906","article-title":"IL-4 Enhances Expression and Function of Surface IgM in CLL Cells","volume":"127","author":"Blunt","year":"2016","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1182\/blood-2015-11-682997","article-title":"IL-4 Rescues Surface IgM Expression in Chronic Lymphocytic Leukemia","volume":"128","author":"Guo","year":"2016","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.3324\/haematol.2021.278644","article-title":"IL4-STAT6 Signaling Induces CD20 in Chronic Lymphocytic Leukemia and This Axis Is Repressed by PI3K\u03b4 Inhibitor Idelalisib","volume":"106","author":"Sandova","year":"2021","journal-title":"Haematologica"},{"key":"ref_58","first-page":"1576","article-title":"Differentiation of Purified Malignant B Cells Induced by PMA or by Activated Normal T Cells","volume":"7","author":"Rensink","year":"1993","journal-title":"Leukemia"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1111\/j.1365-2141.2012.09191.x","article-title":"Mimicking the Tumour Microenvironment: Three Different Co-Culture Systems Induce a Similar Phenotype but Distinct Proliferative Signals in Primary Chronic Lymphocytic Leukaemia Cells","volume":"158","author":"Hamilton","year":"2012","journal-title":"Br. J. Haematol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5071","DOI":"10.1038\/onc.2010.248","article-title":"Dichotomy in NF-\u039aB Signaling and Chemoresistance in Immunoglobulin Variable Heavy-Chain-Mutated versus Unmutated CLL Cells upon CD40\/TLR9 Triggering","volume":"29","author":"Tromp","year":"2010","journal-title":"Oncogene"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1038\/leu.2009.145","article-title":"Different Proliferative and Survival Capacity of CLL-Cells in a Newly Established in Vitro Model for Pseudofollicles","volume":"23","author":"Plander","year":"2009","journal-title":"Leukemia"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"26019","DOI":"10.18632\/oncotarget.25419","article-title":"A Novel Ex Vivo High-Throughput Assay Reveals Antiproliferative Effects of Idelalisib and Ibrutinib in Chronic Lymphocytic Leukemia","volume":"9","author":"Primo","year":"2018","journal-title":"Oncotarget"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41408-021-00429-z","article-title":"Ibrutinib and Venetoclax Target Distinct Subpopulations of CLL Cells: Implication for Residual Disease Eradication","volume":"11","author":"Lu","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"901","DOI":"10.4049\/jimmunol.1403189","article-title":"TLR-9 and IL-15 Synergy Promotes the In Vitro Clonal Expansion of Chronic Lymphocytic Leukemia B Cells","volume":"195","author":"Mongini","year":"2015","journal-title":"J. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.exphem.2010.02.008","article-title":"Heterogeneous Expression and Function of IL-21R and Susceptibility to IL-21\u2212mediated Apoptosis in Follicular Lymphoma Cells","volume":"38","author":"Capaia","year":"2010","journal-title":"Exp. Hematol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Cecco, L.D., Capaia, M., Zupo, S., Cutrona, G., Matis, S., Brizzolara, A., Orengo, A.M., Croce, M., Marchesi, E., and Ferrarini, M. (2015). Interleukin 21 Controls MRNA and MicroRNA Expression in CD40-Activated Chronic Lymphocytic Leukemia Cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134706"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"102948","DOI":"10.18632\/oncotarget.22292","article-title":"Delineating the Distinct Role of AKT in Mediating Cell Survival and Proliferation Induced by CD154 and IL-4\/IL-21 in Chronic Lymphocytic Leukemia","volume":"8","author":"Chapman","year":"2017","journal-title":"Oncotarget"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3708","DOI":"10.1182\/blood-2005-09-3535","article-title":"Interleukin-21 Receptor (IL-21R) Is Up-Regulated by CD40 Triggering and Mediates Proapoptotic Signals in Chronic Lymphocytic Leukemia B Cells","volume":"107","author":"Meazza","year":"2006","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/ncomms1475","article-title":"In-Vitro Derived Germinal Centre B Cells Differentially Generate Memory B or Plasma Cells In Vivo","volume":"2","author":"Nojima","year":"2011","journal-title":"Nat. Commun."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4543","DOI":"10.1038\/s41467-019-12494-x","article-title":"Genetic Modification of Primary Human B Cells to Model High-Grade Lymphoma","volume":"10","author":"Caeser","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1084\/jem.177.1.213","article-title":"Interferon Gamma Inhibits Apoptotic Cell Death in B Cell Chronic Lymphocytic Leukemia","volume":"177","author":"Buschle","year":"1993","journal-title":"J. Exp. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.4049\/jimmunol.2000478","article-title":"Effect of Ibrutinib on the IFN Response of Chronic Lymphocytic Leukemia Cells","volume":"205","author":"Xia","year":"2020","journal-title":"J. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Bauvois, B., Pramil, E., Jondreville, L., Quiney, C., Nguyen-Khac, F., and Susin, S.A. (2021). Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src\/STAT3\/Mcl-1 Signaling Pathway. Biomedicines, 9.","DOI":"10.3390\/biomedicines9020188"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1182\/blood.V87.3.1022.bloodjournal8731022","article-title":"Interleukin-13 Inhibits Interleukin-2-Induced Proliferation and Protects Chronic Lymphocytic Leukemia B Cells from In Vitro Apoptosis","volume":"87","author":"Chaouchi","year":"1996","journal-title":"Blood"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.leukres.2018.01.006","article-title":"Targeting the IL-17\/IL-6 Axis Can Alter Growth of Chronic Lymphocytic Leukemia in Vivo\/in Vitro","volume":"66","author":"Zhu","year":"2018","journal-title":"Leuk. Res."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Ghamlouch, H., Ouled-Haddou, H., Damaj, G., Royer, B., Gubler, B., and Marolleau, J.-P. (2013). A Combination of Cytokines Rescues Highly Purified Leukemic CLL B-Cells from Spontaneous Apoptosis In Vitro. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060370"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4180","DOI":"10.4049\/jimmunol.1800241","article-title":"Chronic Lymphocytic Leukemia\u2013Derived IL-10 Suppresses Antitumor Immunity","volume":"200","author":"Alhakeem","year":"2018","journal-title":"J. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1038\/leu.2017.129","article-title":"Targeting Antigen-Independent Proliferation in Chronic Lymphocytic Leukemia through Differential Kinase Inhibition","volume":"31","author":"Slinger","year":"2017","journal-title":"Leukemia"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1182\/blood.V80.12.3173.3173","article-title":"Responsiveness of Chronic Lymphocytic Leukemia B Cells Activated via Surface Igs or CD40 to B-Cell Tropic Factors","volume":"80","author":"Fluckiger","year":"1992","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1111\/j.1365-2141.2004.05225.x","article-title":"CD40 Stimulation of B-Cell Chronic Lymphocytic Leukaemia Cells Enhances the Anti-Apoptotic Profile, but Also Bid Expression and Cells Remain Susceptible to Autologous Cytotoxic T-Lymphocyte Attack","volume":"127","author":"Kater","year":"2004","journal-title":"Br. J. Haematol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1038\/leu.2014.96","article-title":"Targeting the Proliferative and Chemoresistant Compartment in Chronic Lymphocytic Leukemia by Inhibiting Survivin Protein","volume":"28","author":"Purroy","year":"2014","journal-title":"Leukemia"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"742","DOI":"10.18632\/oncotarget.13557","article-title":"Inhibition of BCR Signaling Using the Syk Inhibitor TAK-659 Prevents Stroma-Mediated Signaling in Chronic Lymphocytic Leukemia Cells","volume":"8","author":"Purroy","year":"2017","journal-title":"Oncotarget"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.cyto.2013.03.023","article-title":"Differential Regulation of B-Cell Proliferation by IL21 in Different Subsets of Chronic Lymphocytic Leukemia","volume":"62","author":"Ghalamfarsa","year":"2013","journal-title":"Cytokine"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"292","DOI":"10.3389\/fimmu.2014.00292","article-title":"TLR9 Ligand (CpG Oligodeoxynucleotide) Induces CLL B-Cells to Differentiate into CD20+ Antibody-Secreting Cells","volume":"5","author":"Ghamlouch","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"5141","DOI":"10.1182\/blood-2008-03-146704","article-title":"C-Abl Kinase Inhibitors Overcome CD40-Mediated Drug Resistance in CLL: Implications for Therapeutic Targeting of Chemoresistant Niches","volume":"112","author":"Hallaert","year":"2008","journal-title":"Blood"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1182\/blood-2015-12-687814","article-title":"High-Content Screening Identifies Kinase Inhibitors That Overcome Venetoclax Resistance in Activated CLL Cells","volume":"128","author":"Oppermann","year":"2016","journal-title":"Blood"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/leu.2008.283","article-title":"Treatment of Primary CLL Cells with Bezafibrate and Medroxyprogesterone Acetate Induces Apoptosis and Represses the Pro-Proliferative Signal of CD40-Ligand, in Part through Increased 15dDelta12,14,PGJ2","volume":"23","author":"Hayden","year":"2009","journal-title":"Leukemia"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1038\/sj.cdd.4402211","article-title":"Crosstalk among Bcl-2 Family Members in B-CLL: Seliciclib Acts via the Mcl-1\/Noxa Axis and Gradual Exhaustion of Bcl-2 Protection","volume":"14","author":"Hallaert","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4403","DOI":"10.1182\/blood-2008-08-173310","article-title":"Concurrent Up-Regulation of BCL-XL and BCL2A1 Induces Approximately 1000-Fold Resistance to ABT-737 in Chronic Lymphocytic Leukemia","volume":"113","author":"Vogler","year":"2009","journal-title":"Blood"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"4188","DOI":"10.1182\/blood.V122.21.4188.4188","article-title":"Possible Mechanisms Of Resistance To The Novel BH3-Mimetic ABT-199 In In Vitro Lymph Node Models of CLL\u2014The Role of Abl and Btk","volume":"122","author":"Thijssen","year":"2013","journal-title":"Blood"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1007\/s00262-021-03043-x","article-title":"Venetoclax-Resistant CLL Cells Show a Highly Activated and Proliferative Phenotype","volume":"71","author":"Elias","year":"2022","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/leu.2011.39","article-title":"CD40 Stimulation Sensitizes CLL Cells to Rituximab-Induced Cell Death","volume":"25","author":"Jak","year":"2011","journal-title":"Leukemia"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5178","DOI":"10.1182\/blood-2011-01-331702","article-title":"CD40 Stimulation Sensitizes CLL Cells to Lysosomal Cell Death Induction by Type II Anti-CD20 MAb GA101","volume":"118","author":"Jak","year":"2011","journal-title":"Blood"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1158\/1078-0432.CCR-16-1662","article-title":"The Dual Syk\/JAK Inhibitor Cerdulatinib Antagonizes B-Cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia","volume":"23","author":"Blunt","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1111\/bjh.15282","article-title":"MEK1\/2 Inhibition by Binimetinib Is Effective as a Single Agent and Potentiates the Actions of Venetoclax and ABT-737 under Conditions That Mimic the Chronic Lymphocytic Leukaemia (CLL) Tumour Microenvironment","volume":"182","author":"Crassini","year":"2018","journal-title":"Br. J. Haematol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5093","DOI":"10.1182\/bloodadvances.2019001369","article-title":"IBL-202 Is Synergistic with Venetoclax in CLL under in Vitro Conditions That Mimic the Tumor Microenvironment","volume":"4","author":"Shen","year":"2020","journal-title":"Blood Adv."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"4441","DOI":"10.1182\/blood-2009-07-233718","article-title":"Diverse Marrow Stromal Cells Protect CLL Cells from Spontaneous and Drug-Induced Apoptosis: Development of a Reliable and Reproducible System to Assess Stromal Cell Adhesion-Mediated Drug Resistance","volume":"114","author":"Kurtova","year":"2009","journal-title":"Blood"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"42130","DOI":"10.18632\/oncotarget.6239","article-title":"Cross-Talk between Chronic Lymphocytic Leukemia (CLL) Tumor B Cells and Mesenchymal Stromal Cells (MSCs): Implications for Neoplastic Cell Survival","volume":"6","author":"Trimarco","year":"2015","journal-title":"Oncotarget"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1038\/s41418-020-00692-w","article-title":"Regulation of Bcl-XL by Non-Canonical NF-\u039aB in the Context of CD40-Induced Drug Resistance in CLL","volume":"28","author":"Haselager","year":"2021","journal-title":"Cell Death Differ."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1158\/1078-0432.CCR-11-1440","article-title":"Tipping the Noxa\/Mcl-1 Balance Overcomes ABT-737 Resistance in Chronic Lymphocytic Leukemia","volume":"18","author":"Tromp","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e458","DOI":"10.3324\/haematol.2018.188680","article-title":"Autologous T-Cell Activation Fosters ABT-199 Resistance in Chronic Lymphocytic Leukemia: Rationale for a Combined Therapy with SYK Inhibitors and Anti-CD20 Monoclonal Antibodies","volume":"103","author":"Colado","year":"2018","journal-title":"Haematologica"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1182\/blood.V92.3.990","article-title":"Triggering of CD40 Antigen Inhibits Fludarabine-Induced Apoptosis in B Chronic Lymphocytic Leukemia Cells","volume":"92","author":"Romano","year":"1998","journal-title":"Blood"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1182\/blood-2021-152222","article-title":"Ibrutinib Treatment in CLL Interrupts CD40 Signaling Capacity and Sensitizes CLL Cells to Venetoclax","volume":"138","author":"Kielbassa","year":"2021","journal-title":"Blood"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1080\/10428194.2017.1403598","article-title":"Ibrutinib and Idelalisib Block Immunophenotypic Changes Associated with the Adhesion and Activation of CLL Cells in the Tumor Microenvironment","volume":"59","author":"Shen","year":"2018","journal-title":"Leuk. Lymphoma"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Delgado, R., Kielbassa, K., ter Burg, J., Klein, C., Trumpfheller, C., de Heer, K., Kater, A.P., and Eldering, E. (2021). Co-Stimulatory versus Cell Death Aspects of Agonistic CD40 Monoclonal Antibody Selicrelumab in Chronic Lymphocytic Leukemia. Cancers, 13.","DOI":"10.3390\/cancers13123084"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/j.1365-2141.2011.08794.x","article-title":"Bone Marrow Stromal Cells Protect Lymphoma B-Cells from Rituximab-Induced Apoptosis and Targeting Integrin \u03b1-4-\u03b2-1 (VLA-4) with Natalizumab Can Overcome This Resistance","volume":"155","author":"Mraz","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"4497","DOI":"10.1182\/blood-2009-07-233692","article-title":"Spleen Tyrosine Kinase Inhibition Prevents Chemokine- and Integrin-Mediated Stromal Protective Effects in Chronic Lymphocytic Leukemia","volume":"115","author":"Buchner","year":"2010","journal-title":"Blood"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"4569","DOI":"10.1182\/blood-2009-09-245811","article-title":"The JAK3-Selective Inhibitor PF-956980 Reverses the Resistance to Cytotoxic Agents Induced by Interleukin-4 Treatment of Chronic Lymphocytic Leukemia Cells: Potential for Reversal of Cytoprotection by the Microenvironment","volume":"116","author":"Steele","year":"2010","journal-title":"Blood"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"591577","DOI":"10.3389\/fonc.2020.591577","article-title":"Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies","volume":"10","author":"Ondrisova","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"4723","DOI":"10.1182\/blood-2007-07-099531","article-title":"IL-21 Mediates Apoptosis through up-Regulation of the BH3 Family Member BIM and Enhances Both Direct and Antibody-Dependent Cellular Cytotoxicity in Primary Chronic Lymphocytic Leukemia Cells In Vitro","volume":"111","author":"Gowda","year":"2008","journal-title":"Blood"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1182\/blood-2012-02-411678","article-title":"Multiple Inhibitory Ligands Induce Impaired T-Cell Immunologic Synapse Function in Chronic Lymphocytic Leukemia That Can Be Blocked with Lenalidomide: Establishing a Reversible Immune Evasion Mechanism in Human Cancer","volume":"120","author":"Ramsay","year":"2012","journal-title":"Blood"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1158\/2326-6066.CIR-15-0291","article-title":"Lenalidomide Induces Interleukin-21 Production by T Cells and Enhances IL21-Mediated Cytotoxicity in Chronic Lymphocytic Leukemia B Cells","volume":"4","author":"Browning","year":"2016","journal-title":"Cancer Immunol. Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/bjh.12630","article-title":"Phase IA\/II, Multicentre, Open-Label Study of the CD40 Antagonistic Monoclonal Antibody Lucatumumab in Adult Patients with Advanced Non-Hodgkin or Hodgkin Lymphoma","volume":"164","author":"Fanale","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"607608","DOI":"10.3389\/fonc.2020.607608","article-title":"Modeling the Leukemia Microenviroment In Vitro","volume":"10","author":"Scielzo","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1084\/jem.20172139","article-title":"Modeling the Human Bone Marrow Niche in Mice: From Host Bone Marrow Engraftment to Bioengineering Approaches","volume":"215","author":"Abarrategi","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2949","DOI":"10.1182\/blood-2016-05-719021","article-title":"Establishing Human Leukemia Xenograft Mouse Models by Implanting Human Bone Marrow\u2013like Scaffold-Based Niches","volume":"128","author":"Antonelli","year":"2016","journal-title":"Blood"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/MOH.0000000000000356","article-title":"Creating Artificial Lymphoid Tissues to Study Immunity and Hematological Malignancies","volume":"24","author":"Shah","year":"2017","journal-title":"Curr. Opin. Hematol"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"119665","DOI":"10.1016\/j.biomaterials.2019.119665","article-title":"Injectable, Scalable 3D Tissue-Engineered Model of Marrow Hematopoiesis","volume":"232","author":"Tavakol","year":"2020","journal-title":"Biomaterials"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.actbio.2018.03.028","article-title":"Current Approaches in Biomaterial-Based Hematopoietic Stem Cell Niches","volume":"72","author":"Bello","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"639572","DOI":"10.3389\/fimmu.2021.639572","article-title":"3D Bioprinting Allows the Establishment of Long-Term 3D Culture Model for Chronic Lymphocytic Leukemia Cells","volume":"12","author":"Sbrana","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Svozilov\u00e1, H., Plichta, Z., Proks, V., Studen\u00e1, R., Baloun, J., Doubek, M., Posp\u00ed\u0161ilov\u00e1, \u0160., and Hor\u00e1k, D. (2021). RGDS-Modified Superporous Poly(2-Hydroxyethyl Methacrylate)-Based Scaffolds as 3D In Vitro Leukemia Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052376"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.biomaterials.2018.02.039","article-title":"A Synthetic Stroma-Free Germinal Center Niche for Efficient Generation of Humoral Immunity Ex Vivo","volume":"164","author":"Roh","year":"2018","journal-title":"Biomaterials"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nprot.2016.157","article-title":"Immuno-Engineered Organoids for Regulating the Kinetics of B-Cell Development and Antibody Production","volume":"12","author":"Purwada","year":"2017","journal-title":"Nat. Protoc."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"3607","DOI":"10.1182\/blood-2013-12-544569","article-title":"Development and Characterization of a Physiologically Relevant Model of Lymphocyte Migration in Chronic Lymphocytic Leukemia","volume":"123","author":"Walsby","year":"2014","journal-title":"Blood"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1182\/blood-2016-01-683128","article-title":"Phenotype and Immune Function of Lymph Node and Peripheral Blood CLL Cells Are Linked to Transendothelial Migration","volume":"128","author":"Pasikowska","year":"2016","journal-title":"Blood"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.3324\/haematol.2020.248112","article-title":"Three-Dimensional Co-Culture Model of Chronic Lymphocytic Leukemia Bone Marrow Microenvironment Predicts Patient-Specific Response to Mobilizing Agents","volume":"106","author":"Barbaglio","year":"2021","journal-title":"Haematologica"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"5372","DOI":"10.1182\/bloodadvances.2020003949","article-title":"A Novel 3D Culture Model Recapitulates Primary FL B-Cell Features and Promotes Their Survival","volume":"5","author":"Lamaison","year":"2021","journal-title":"Blood Adv."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1182\/blood-2014-05-577122","article-title":"Mouse Models in the Study of Chronic Lymphocytic Leukemia Pathogenesis and Therapy","volume":"124","author":"Simonetti","year":"2014","journal-title":"Blood"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"e2071","DOI":"10.1038\/cddis.2015.419","article-title":"TCL1 Transgenic Mouse Model as a Tool for the Study of Therapeutic Targets and Microenvironment in Human B-Cell Chronic Lymphocytic Leukemia","volume":"7","author":"Bresin","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"6955","DOI":"10.1073\/pnas.102181599","article-title":"Human Chronic Lymphocytic Leukemia Modeled in Mouse by Targeted TCL1 Expression","volume":"99","author":"Bichi","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"6250","DOI":"10.1073\/pnas.0901166106","article-title":"E\u00b5-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_132","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1038\/leu.2011.111","article-title":"Development of CLL in the TCL1 Transgenic Mouse Model Is Associated with Severe Skewing of the T-Cell Compartment Homologous to Human CLL","volume":"25","author":"Hofbauer","year":"2011","journal-title":"Leukemia"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1038\/leu.2015.307","article-title":"CD4+ T Cells, but Not Non-Classical Monocytes, Are Dispensable for the Development of Chronic Lymphocytic Leukemia in the TCL1-Tg Murine Model","volume":"30","author":"Kocher","year":"2016","journal-title":"Leukemia"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1182\/bloodadvances.2020003795","article-title":"CD4+ T Cells Sustain Aggressive Chronic Lymphocytic Leukemia in E\u03bc-TCL1 Mice through a CD40L-Independent Mechanism","volume":"5","author":"Grioni","year":"2021","journal-title":"Blood Adv."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"16600","DOI":"10.1073\/pnas.0407541101","article-title":"TNF Receptor-Associated Factor (TRAF) Domain and Bcl-2 Cooperate to Induce Small B Cell Lymphoma\/Chronic Lymphocytic Leukemia in Transgenic Mice","volume":"101","author":"Zapata","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"3749","DOI":"10.1182\/blood.V100.10.3749","article-title":"Tumor Necrosis Factor Receptor-Associated Factor 1 Gene Overexpression in B-Cell Chronic Lymphocytic Leukemia: Analysis of NF-\u039aB\/Rel\u2013Regulated Inhibitors of Apoptosis","volume":"100","author":"Munzert","year":"2002","journal-title":"Blood"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1111\/j.1600-065X.2009.00782.x","article-title":"Molecular Mechanism and Function of CD40\/CD40L Engagement in the Immune System","volume":"229","author":"Elgueta","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S1074-7613(00)80390-8","article-title":"TRAF2 Is Essential for JNK but Not NF-KappaB Activation and Regulates Lymphocyte Proliferation and Survival","volume":"7","author":"Lee","year":"1997","journal-title":"Immunity"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1182\/blood.V89.6.2210","article-title":"A Model for Human B-Chronic Lymphocytic Leukemia in Human\/Mouse Radiation Chimera: Evidence for Tumor-Mediated Suppression of Antibody Production in Low-Stage Disease","volume":"89","author":"Shimoni","year":"1997","journal-title":"Blood"},{"key":"ref_140","first-page":"5968","article-title":"Autologous T Cells Control B-Chronic Lymphocytic Leukemia Tumor Progression in Human\u2192Mouse Radiation Chimera","volume":"59","author":"Shimoni","year":"1999","journal-title":"Cancer Res."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"8653","DOI":"10.1158\/0008-5472.CAN-07-1198","article-title":"A Novel Nonobese Diabetic\/Severe Combined Immunodeficient Xenograft Model for Chronic Lymphocytic Leukemia Reflects Important Clinical Characteristics of the Disease","volume":"67","author":"Ebeling","year":"2007","journal-title":"Cancer Res."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1600-0609.2011.01626.x","article-title":"Investigating the Role of CD38 and Functionally Related Molecular Risk Factors in the CLL NOD\/SCID Xenograft Model","volume":"87","author":"Aydin","year":"2011","journal-title":"Eur. J. Haematol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"5463","DOI":"10.1182\/blood-2010-12-324210","article-title":"A Novel Adoptive Transfer Model of Chronic Lymphocytic Leukemia Suggests a Key Role for T Lymphocytes in the Disease","volume":"117","author":"Bagnara","year":"2011","journal-title":"Blood"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"627020","DOI":"10.3389\/fimmu.2021.627020","article-title":"A Detailed Analysis of Parameters Supporting the Engraftment and Growth of Chronic Lymphocytic Leukemia Cells in Immune-Deficient Mice","volume":"12","author":"Patten","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_145","first-page":"1401","article-title":"T-Cell Number and Subtype Influence the Disease Course of Primary Chronic Lymphocytic Leukaemia Xenografts in Alymphoid Mice","volume":"8","author":"Oldreive","year":"2015","journal-title":"Dis. Models Mech."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Decker, S., Zwick, A., Khaja Saleem, S., Kissel, S., Rettig, A., Aumann, K., and Dierks, C. (2019). Optimized Xenograft Protocol for Chronic Lymphocytic Leukemia Results in High Engraftment Efficiency for All CLL Subgroups. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246277"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"44749","DOI":"10.18632\/oncotarget.17432","article-title":"Dynamic Changes in Clonal Cytogenetic Architecture during Progression of Chronic Lymphocytic Leukemia in Patients and Patient-Derived Murine Xenografts","volume":"8","author":"Davies","year":"2017","journal-title":"Oncotarget"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1038\/leu.2013.131","article-title":"Modeling Tumor-Host Interactions of Chronic Lymphocytic Leukemia in Xenografted Mice to Study Tumor Biology and Evaluate Targeted Therapy","volume":"27","author":"Herman","year":"2013","journal-title":"Leukemia"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"e86288","DOI":"10.1172\/jci.insight.86288","article-title":"Chronic Lymphocytic Leukemia Cells Diversify and Differentiate in Vivo via a Nonclassical Th1-Dependent, Bcl-6-Deficient Process","volume":"1","author":"Patten","year":"2016","journal-title":"JCI Insight"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1538\/expanim.19-0024","article-title":"Comparison of Biological Features between Severely Immuno-Deficient NOD\/Shi-Scid Il2rgnull and NOD\/LtSz-Scid Il2rgnull Mice","volume":"68","author":"Nagatani","year":"2019","journal-title":"Exp. Anim."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ccr.2011.06.029","article-title":"Self-Renewing Hematopoietic Stem Cell Is the Primary Target in Pathogenesis of Human Chronic Lymphocytic Leukemia","volume":"20","author":"Kikushige","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1182\/bloodadvances.2017005892","article-title":"Patient-Derived Xenografts of Low-Grade B-Cell Lymphomas Demonstrate Roles of the Tumor Microenvironment","volume":"1","author":"Burack","year":"2017","journal-title":"Blood Adv."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/13\/3087\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:38:44Z","timestamp":1760139524000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/13\/3087"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,23]]},"references-count":152,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["cancers14133087"],"URL":"https:\/\/doi.org\/10.3390\/cancers14133087","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,23]]}}}