{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:27:44Z","timestamp":1790807264804,"version":"4.1.0"},"reference-count":199,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T00:00:00Z","timestamp":1698278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"Associazione Italiana Ricerca sul Cancro (AIRC) Special 5 \u00d7 1000 Program Metastases","doi-asserted-by":"publisher","award":["21198"],"award-info":[{"award-number":["21198"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007076","name":"Associazione Italiana Ricerca sul Cancro (AIRC) Special 5 \u00d7 1000 Program Metastases","doi-asserted-by":"publisher","award":["800924"],"award-info":[{"award-number":["800924"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"name":"iCARE-2 2019 program","award":["21198"],"award-info":[{"award-number":["21198"]}]},{"name":"iCARE-2 2019 program","award":["800924"],"award-info":[{"award-number":["800924"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Chronic lymphocytic leukemia (CLL) is a B-cell malignancy whose progression largely depends on the lymph node and bone marrow microenvironment. Indeed, CLL cells actively proliferate in specific regions of these anatomical compartments, known as proliferation centers, while being quiescent in the blood stream. Hence, CLL cell adhesion and migration into these protective niches are critical for CLL pathophysiology. CLL cells are lodged in their microenvironment through a series of molecular interactions that are mediated by cellular adhesion molecules and their counter receptors. The importance of these adhesion molecules in the clinic is demonstrated by the correlation between the expression levels of some of them, in particular CD49d, and the prognostic likelihood. Furthermore, novel therapeutic agents, such as ibrutinib, impair the functions of these adhesion molecules, leading to an egress of CLL cells from the lymph nodes and bone marrow into the circulation together with an inhibition of homing into these survival niches, thereby preventing disease progression. Several adhesion molecules have been shown to participate in CLL adhesion and migration. Their importance also stems from the observation that they are involved in promoting, directly or indirectly, survival signals that sustain CLL proliferation and limit the efficacy of standard and novel chemotherapeutic drugs, a process known as cell adhesion-mediated drug resistance. In this respect, many studies have elucidated the molecular mechanisms underlying cell adhesion-mediated drug resistance, which have highlighted different signaling pathways that may represent potential therapeutic targets. Here, we review the role of the microenvironment and the adhesion molecules that have been shown to be important in CLL and their impact on transendothelial migration and cell-mediated drug resistance. We also discuss how novel therapeutic compounds modulate the function of this important class of molecules.<\/jats:p>","DOI":"10.3390\/cancers15215160","type":"journal-article","created":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T09:56:36Z","timestamp":1698400596000},"page":"5160","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The Role of the Microenvironment and Cell Adhesion Molecules in Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1554-1497","authenticated-orcid":false,"given":"Marina","family":"Cerreto","sequence":"first","affiliation":[{"name":"Hematology, Department of Translational and Precision Medicine, Sapienza University, 00100 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Fo\u00e0","sequence":"additional","affiliation":[{"name":"Hematology, Department of Translational and Precision Medicine, Sapienza University, 00100 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4321-9005","authenticated-orcid":false,"given":"Alessandro","family":"Natoni","sequence":"additional","affiliation":[{"name":"Hematology, Department of Translational and Precision Medicine, Sapienza University, 00100 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1182\/blood.V94.6.1848","article-title":"Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia","volume":"94","author":"Hamblin","year":"1999","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17008","DOI":"10.1038\/nrdp.2017.8","article-title":"Chronic lymphocytic leukaemia","volume":"3","author":"Kipps","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1172\/JCI23409","article-title":"In Vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells","volume":"115","author":"Messmer","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1097\/00000478-199801000-00006","article-title":"Lymph node histology in typical and atypical chronic lymphocytic leukemia","volume":"22","author":"Bonato","year":"1998","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/S0046-8177(99)90089-8","article-title":"High expression of CD23 in the proliferation centers of chronic lymphocytic leukemia in lymph nodes and spleen","volume":"30","author":"Lampert","year":"1999","journal-title":"Hum. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1182\/blood.V88.1.268.268","article-title":"Expression of the retinoblastoma protein in low-grade B-cell lymphoma: Relationship to cyclin D1","volume":"88","author":"Zukerberg","year":"1996","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"92","DOI":"10.5858\/2005-129-92-CLSLLW","article-title":"Chronic lymphocytic leukemia\/small lymphocytic lymphoma with trisomy 12 and focal cyclin d1 expression: A potential diagnostic pitfall","volume":"129","author":"Vance","year":"2005","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1111\/j.1349-7006.2011.02046.x","article-title":"Cyclin D2 is overexpressed in proliferation centers of chronic lymphocytic leukemia\/small lymphocytic lymphoma","volume":"102","author":"Igawa","year":"2011","journal-title":"Cancer Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1158\/1535-7163.MCT-10-1119","article-title":"Mechanisms of action of a dual Cdc7\/Cdk9 kinase inhibitor against quiescent and proliferating CLL cells","volume":"10","author":"Natoni","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0065-230X(00)79005-1","article-title":"The indispensable role of microenvironment in the natural history of low-grade B-cell neoplasms","volume":"79","author":"Ghia","year":"2000","journal-title":"Adv. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"96","DOI":"10.3892\/etm.2020.9528","article-title":"An overview of the tumor microenvironment, from cells to complex networks (Review)","volume":"21","author":"Farc","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1158\/1078-0432.CCR-13-0226","article-title":"Molecular pathways: Targeting the microenvironment in chronic lymphocytic leukemia-focus on the B-cell receptor","volume":"20","author":"Burger","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1080\/10428190290011921","article-title":"Chemokine receptors and stromal cells in the homing and homeostasis of chronic lymphocytic leukemia B cells","volume":"43","author":"Burger","year":"2002","journal-title":"Leuk. Lymphoma"},{"key":"ref_15","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_16","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_17","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.humpath.2005.09.029","article-title":"The proliferation center microenvironment and prognostic markers in chronic lymphocytic leukemia\/small lymphocytic lymphoma","volume":"37","author":"Soma","year":"2006","journal-title":"Hum. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"592205","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_19","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1089\/scd.2012.0255","article-title":"Study of the quantitative, functional, cytogenetic, and immunoregulatory properties of bone marrow mesenchymal stem cells in patients with B-cell chronic lymphocytic leukemia","volume":"22","author":"Pontikoglou","year":"2013","journal-title":"Stem Cells Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.coi.2021.06.014","article-title":"BAFF signaling in health and disease","volume":"71","author":"Schweighoffer","year":"2021","journal-title":"Curr. Opin. Immunol."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1046\/j.1365-2141.1999.01219.x","article-title":"IL4 production and increased CD30 expression by a unique CD8+ T-cell subset in B-cell chronic lymphocytic leukaemia","volume":"104","author":"Reato","year":"1999","journal-title":"Br. J. Haematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1080\/1042819031000068007","article-title":"IL-4 biology: Impact on normal and leukemic CLL B cells","volume":"44","author":"Kay","year":"2003","journal-title":"Leuk. Lymphoma"},{"key":"ref_24","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_25","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_26","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.4049\/jimmunol.1800591","article-title":"Mechanistic Insights into CpG DNA and IL-15 Synergy in Promoting B Cell Chronic Lymphocytic Leukemia Clonal Expansion","volume":"201","author":"Gupta","year":"2018","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.4049\/jimmunol.1801142","article-title":"Mechanism for IL-15-Driven B Cell Chronic Lymphocytic Leukemia Cycling: Roles for AKT and STAT5 in Modulating Cyclin D2 and DNA Damage Response Proteins","volume":"202","author":"Gupta","year":"2019","journal-title":"J. Immunol."},{"key":"ref_28","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_29","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_30","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_31","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_32","first-page":"e302","article-title":"Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors","volume":"100","author":"Thijssen","year":"2015","journal-title":"Haematologica"},{"key":"ref_33","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_34","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0145-2126(88)90137-3","article-title":"Release of interleukin-2-like material by B-chronic lymphocytic leukemia cells. An autocrine or paracrine model of production and utilization?","volume":"12","author":"Giovarelli","year":"1988","journal-title":"Leuk. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1182\/blood.V84.1.220.220","article-title":"Cytokine gene expression in B-cell chronic lymphocytic leukemia: Evidence of constitutive interleukin-8 (IL-8) mRNA expression and secretion of biologically active IL-8 protein","volume":"84","author":"Carbone","year":"1994","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4382","DOI":"10.1182\/blood.V87.10.4382.bloodjournal87104382","article-title":"Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion","volume":"87","author":"Mariani","year":"1996","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1182\/blood.V76.2.393.bloodjournal762393","article-title":"Production of tumor necrosis factor-alpha by B-cell chronic lymphocytic leukemia cells: A possible regulatory role of TNF in the progression of the disease","volume":"76","author":"Foa","year":"1990","journal-title":"Blood"},{"key":"ref_38","first-page":"226","article-title":"Interleukin-2 enhances the production of tumor necrosis factor-alpha in activated B-type chronic lymphocytic leukemia (B-CLL) cells","volume":"7","author":"Larsson","year":"1993","journal-title":"Leukemia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.3389\/fonc.2020.01422","article-title":"Importance of Crosstalk Between Chronic Lymphocytic Leukemia Cells and the Stromal Microenvironment: Direct Contact, Soluble Factors, and Extracellular Vesicles","volume":"10","author":"Dubois","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_40","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_41","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1182\/blood-2014-07-589069","article-title":"Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia","volume":"125","author":"Audrito","year":"2015","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1182\/blood-2013-10-529610","article-title":"Extracellular HMGB1 promotes differentiation of nurse-like cells in chronic lymphocytic leukemia","volume":"123","author":"Jia","year":"2014","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4180","DOI":"10.4049\/jimmunol.1800241","article-title":"Chronic Lymphocytic Leukemia-Derived IL-10 Suppresses Antitumor Immunity","volume":"200","author":"Alhakeem","year":"2018","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1038\/sj.leu.2405015","article-title":"Tumor-derived IL-6 may contribute to the immunological defect in CLL","volume":"22","author":"Buggins","year":"2008","journal-title":"Leukemia"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.1038\/s41375-021-01217-1","article-title":"Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia","volume":"35","author":"Rivas","year":"2021","journal-title":"Leukemia"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Nistic\u00f2, N., Maisano, D., Iaccino, E., Vecchio, E., Fiume, G., Rotundo, S., Quinto, I., and Mimmi, S. (2020). Role of Chronic Lymphocytic Leukemia (CLL)-Derived Exosomes in Tumor Progression and Survival. Pharmaceuticals, 13.","DOI":"10.3390\/ph13090244"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"B\u00f6ttcher, M., B\u00f6ttcher-Loschinski, R., Kahlfuss, S., Aigner, M., Gie\u00dfl, A., Mackensen, A., Schl\u00f6tzer-Schrehardt, U., T\u00fcting, T., Bruns, H., and Mougiakakos, D. (2022). CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints. Cells, 11.","DOI":"10.3390\/cells11142176"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1182\/blood-2014-12-618025","article-title":"Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts","volume":"126","author":"Paggetti","year":"2015","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"123","DOI":"10.2119\/molmed.2014.00214","article-title":"Opposite Prognostic Significance of Cellular and Serum Circulating MicroRNA-150 in Patients with Chronic Lymphocytic Leukemia","volume":"21","author":"Stamatopoulos","year":"2015","journal-title":"Mol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1182\/blood-2009-09-242719","article-title":"Circulating microvesicles in B-cell chronic lymphocytic leukemia can stimulate marrow stromal cells: Implications for disease progression","volume":"115","author":"Ghosh","year":"2010","journal-title":"Blood"},{"key":"ref_51","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_52","doi-asserted-by":"crossref","first-page":"3271","DOI":"10.1182\/blood-2012-03-417519","article-title":"Dysfunctional V\u03b39V\u03b42 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells","volume":"120","author":"Coscia","year":"2012","journal-title":"Blood"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.3324\/haematol.2020.268037","article-title":"Targeting the tumor microenvironment in chronic lymphocytic leukemia","volume":"106","author":"Svanberg","year":"2021","journal-title":"Haematologica"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3658","DOI":"10.1182\/blood.V94.11.3658","article-title":"Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells","volume":"94","author":"Burger","year":"1999","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1172\/JCI11092","article-title":"Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism","volume":"107","author":"Burger","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ccr.2012.12.003","article-title":"Protein kinase c-\u03b2-dependent activation of NF-\u03baB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo","volume":"23","author":"Lutzny","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1080\/10428199909169609","article-title":"Adhesion to bone marrow stroma inhibits apoptosis of chronic lymphocytic leukemia cells","volume":"35","author":"Lagneaux","year":"1999","journal-title":"Leuk. Lymphoma"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1080\/10245332.2001.11746544","article-title":"Adhesion of B-Cell Chronic Lymphocytic Leukemia Cells to Marrow Stromal Cells is Mediated by \u03b14\u03b21 but not \u03b22\u03b1L Integrin: MSC also Prevent Apoptosis of B-CLL Cells","volume":"5","author":"Lee","year":"2001","journal-title":"Hematology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/ncb2432","article-title":"Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia","volume":"14","author":"Zhang","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4098","DOI":"10.1182\/blood-2002-08-2512","article-title":"Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents","volume":"101","author":"Zhou","year":"2003","journal-title":"Blood"},{"key":"ref_61","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":"2015","journal-title":"Oncotarget"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/bjh.13286","article-title":"Bone marrow stromal mesenchymal cells induce down regulation of CD20 expression on B-CLL: Implications for rituximab resistance in CLL","volume":"169","author":"Marquez","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1002\/jcp.30662","article-title":"Follicular dendritic cells","volume":"237","author":"Saber","year":"2022","journal-title":"J. Cell. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.smim.2007.12.001","article-title":"Follicular dendritic cell networks of primary follicles and germinal centers: Phenotype and function","volume":"20","author":"Allen","year":"2008","journal-title":"Semin. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1158\/2159-8290.CD-14-0096","article-title":"Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B-cell activation and proliferation","volume":"4","author":"Heinig","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1182\/blood.V100.5.1795.h81702001795_1795_1801","article-title":"Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1","volume":"100","author":"Pedersen","year":"2002","journal-title":"Blood"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1182\/blood-2002-05-1339","article-title":"CD100\/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes","volume":"101","author":"Granziero","year":"2003","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1182\/blood.V99.3.1030","article-title":"Distinctive features of \u201cnurselike\u201d cells that differentiate in the context of chronic lymphocytic leukemia","volume":"99","author":"Tsukada","year":"2002","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.3109\/10428194.2014.991731","article-title":"Nurse like cells: Chronic lymphocytic leukemia associated macrophages","volume":"56","author":"Boissard","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/j.1365-2141.2011.08747.x","article-title":"Nurse-like cells show deregulated expression of genes involved in immunocompetence","volume":"154","author":"Bhattacharya","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.3324\/haematol.2013.091405","article-title":"Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages","volume":"99","author":"Giannoni","year":"2014","journal-title":"Haematologica"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3316","DOI":"10.1182\/blood-2007-05-089409","article-title":"Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia","volume":"110","author":"Niedermeier","year":"2007","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1182\/blood-2004-03-0889","article-title":"Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1\u03b1","volume":"106","author":"Nishio","year":"2005","journal-title":"Blood"},{"key":"ref_74","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_75","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1182\/blood-2004-10-3873","article-title":"CD38 and CD100 lead a network of surface receptors relaying positive signals for B-CLL growth and survival","volume":"105","author":"Deaglio","year":"2005","journal-title":"Blood"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/j.1365-2141.2010.08152.x","article-title":"Monocytes\/macrophages but not T lymphocytes are the major targets of the CCL3\/CCL4 chemokines produced by CD38+CD49d+ chronic lymphocytic leukaemia cells","volume":"150","author":"Zucchetto","year":"2010","journal-title":"Br. J. Haematol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4001","DOI":"10.1158\/0008-5472.CAN-08-4173","article-title":"CD38\/CD31, the CCL3 and CCL4 chemokines, and CD49d\/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival","volume":"69","author":"Zucchetto","year":"2009","journal-title":"Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1038\/onc.2017.365","article-title":"Neurotensin receptor type 2 protects B-cell chronic lymphocytic leukemia cells from apoptosis","volume":"37","author":"Abbaci","year":"2018","journal-title":"Oncogene"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"12572","DOI":"10.1038\/s41598-020-69307-1","article-title":"BDNF belongs to the nurse-like cell secretome and supports survival of B chronic lymphocytic leukemia cells","volume":"10","author":"Talbot","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4691","DOI":"10.1182\/bloodadvances.2021006169","article-title":"Nurselike cells sequester B cells in disorganized lymph nodes in chronic lymphocytic leukemia via alternative production of CCL21","volume":"6","author":"Zaaboub","year":"2022","journal-title":"Blood Adv."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4824","DOI":"10.1096\/fj.201701452RR","article-title":"ZAP70 expression enhances chemokine-driven chronic lymphocytic leukemia cell migration and arrest by valency regulation of integrins","volume":"32","author":"Laufer","year":"2018","journal-title":"FASEB J."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.hoc.2013.01.003","article-title":"Understanding the immunodeficiency in chronic lymphocytic leukemia: Potential clinical implications","volume":"27","author":"Riches","year":"2013","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_83","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_84","first-page":"277","article-title":"T-cell functional abnormality in B-chronic lymphocytic leukaemia: Evidence of a defect of the T-helper subset","volume":"54","author":"Lauria","year":"1983","journal-title":"Br. J. Haematol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1038\/sj.leu.2403907","article-title":"Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia","volume":"19","author":"Motta","year":"2005","journal-title":"Leukemia"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.celrep.2016.02.084","article-title":"Human Cytotoxic T Lymphocytes Form Dysfunctional Immune Synapses with B Cells Characterized by Non-Polarized Lytic Granule Release","volume":"15","author":"Kabanova","year":"2016","journal-title":"Cell Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6250","DOI":"10.1073\/pnas.0901166106","article-title":"E\u03bc-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_88","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_89","first-page":"4497","article-title":"The circulating dendritic cell compartment in patients with chronic lymphocytic leukemia is severely defective and unable to stimulate an effective T-cell response","volume":"63","author":"Orsini","year":"2003","journal-title":"Cancer Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1182\/blood.V62.6.1289.1289","article-title":"Immunohistologic study of bone marrow involvement in B-chronic lymphocytic leukemia","volume":"62","author":"Pizzolo","year":"1983","journal-title":"Blood"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1002\/1521-4141(200205)32:5<1403::AID-IMMU1403>3.0.CO;2-Y","article-title":"Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L+ T cells by producing CCL22","volume":"32","author":"Ghia","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1080\/10428190701447353","article-title":"Separate cell culture conditions to promote proliferation or quiescent cell survival in chronic lymphocytic leukemia","volume":"48","author":"Willimott","year":"2007","journal-title":"Leuk. Lymphoma"},{"key":"ref_93","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_94","doi-asserted-by":"crossref","first-page":"6071","DOI":"10.4049\/jimmunol.1102066","article-title":"Stromal endothelial cells establish a bidirectional crosstalk with chronic lymphocytic leukemia cells through the TNF-related factors BAFF, APRIL, and CD40L","volume":"188","author":"Cols","year":"2012","journal-title":"J. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1016\/j.humpath.2011.02.027","article-title":"Cross-talk between chronic lymphocytic leukemia cells and bone marrow endothelial cells: Role of signal transducer and activator of transcription 3","volume":"42","author":"Badoux","year":"2011","journal-title":"Hum. Pathol."},{"key":"ref_96","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_97","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_98","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1038\/sj.leu.2401825","article-title":"Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia","volume":"14","author":"Kini","year":"2000","journal-title":"Leukemia"},{"key":"ref_99","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_100","first-page":"263","article-title":"Bone marrow angiogenesis and proliferation in B-cell chronic lymphocytic leukemia","volume":"26","author":"Wolowiec","year":"2004","journal-title":"Anal. Quant. Cytol. Histol."},{"key":"ref_101","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_102","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1182\/blood.V97.1.242","article-title":"Interleukin-6 dimers produced by endothelial cells inhibit apoptosis of B-chronic lymphocytic leukemia cells","volume":"97","author":"Moreno","year":"2001","journal-title":"Blood"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"952","DOI":"10.3324\/haematol.2011.054924","article-title":"Physical contact with endothelial cells through \u03b21- and \u03b22- integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells","volume":"97","author":"Maffei","year":"2012","journal-title":"Haematologica"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"7523","DOI":"10.1158\/0008-5472.CAN-10-1634","article-title":"Interaction with vascular endothelium enhances survival in primary chronic lymphocytic leukemia cells via NF-\u03baB activation and de novo gene transcription","volume":"70","author":"Buggins","year":"2010","journal-title":"Cancer Res."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Maffei, R., Bulgarelli, J., Fiorcari, S., Martinelli, S., Castelli, I., Valenti, V., Rossi, D., Bonacorsi, G., Zucchini, P., and Potenza, L. (2014). Endothelin-1 promotes survival and chemoresistance in chronic lymphocytic leukemia B cells through ETA receptor. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098818"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/s41392-021-00544-0","article-title":"Extracellular matrix and its therapeutic potential for cancer treatment","volume":"6","author":"Huang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"6850","DOI":"10.1111\/febs.15776","article-title":"A guide to the composition and functions of the extracellular matrix","volume":"288","author":"Karamanos","year":"2021","journal-title":"FEBS J."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.matbio.2007.04.003","article-title":"Laminin-332 (Laminin-5) is the major motility ligand for B cell chronic lymphocytic leukemia","volume":"26","author":"Spessotto","year":"2007","journal-title":"Matrix Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1189\/jlb.71.3.495","article-title":"Engagement of \u03b14\u03b21 integrin by fibronectin induces in vitro resistance of B chronic lymphocytic leukemia cells to fludarabine","volume":"71","author":"Casanova","year":"2002","journal-title":"J. Leukoc. Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1146\/annurev-pathol-011110-130224","article-title":"Mechanisms of leukocyte transendothelial migration","volume":"6","author":"Muller","year":"2011","journal-title":"Annu. Rev. Pathol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"4377","DOI":"10.1111\/j.1742-4658.2006.05437.x","article-title":"Selectins and glycosyltransferases in leukocyte rolling in vivo","volume":"273","author":"Sperandio","year":"2006","journal-title":"FEBS J."},{"key":"ref_112","first-page":"165","article-title":"Constitutive expression of E-selectin and vascular cell adhesion molecule-1 on endothelial cells of hematopoietic tissues","volume":"148","author":"Schweitzer","year":"1996","journal-title":"Am. J. Pathol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/379266a0","article-title":"Adhesion through L-selectin requires a threshold hydrodynamic shear","volume":"379","author":"Finger","year":"1996","journal-title":"Nature"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1093\/cvr\/cvv154","article-title":"Selectins: Initiators of leucocyte adhesion and signalling at the vascular wall","volume":"107","author":"McEver","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0925-4439(99)00071-X","article-title":"Leukocyte adhesion deficiency type II","volume":"1455","author":"Becker","year":"1999","journal-title":"Biochim. Biophys Acta (BBA) Mol. Basis Dis."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/bs.acr.2022.07.001","article-title":"The biology of E-selectin ligands in leukemogenesis","volume":"157","author":"Ales","year":"2023","journal-title":"Adv. Cancer Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/nri2156","article-title":"Getting to the site of inflammation: The leukocyte adhesion cascade updated","volume":"7","author":"Ley","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0092-8674(02)00971-6","article-title":"Integrins: Bidirectional, allosteric signaling machines","volume":"110","author":"Hynes","year":"2002","journal-title":"Cell"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1146\/annurev.immunol.25.022106.141618","article-title":"Structural basis of integrin regulation and signaling","volume":"25","author":"Luo","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1126\/science.1084174","article-title":"Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins","volume":"301","author":"Kim","year":"2003","journal-title":"Science"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3109\/10428190109097671","article-title":"Impaired transendothelial migration of B-CLL lymphocytes: A defect linked to low L-selectin expression","volume":"42","author":"Gu","year":"2001","journal-title":"Leuk. Lymphoma"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/j.1365-2141.1999.01278.x","article-title":"Transendothelial migration of lymphocytes in chronic lymphocytic leukaemia is impaired and involved down-regulation of both L-selectin and CD23","volume":"105","author":"Chen","year":"1999","journal-title":"Br. J. Haematol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"6387","DOI":"10.1158\/0008-5472.CAN-08-4750","article-title":"Down-regulation of CXCR4 and CD62L in chronic lymphocytic leukemia cells is triggered by B-cell receptor ligation and associated with progressive disease","volume":"69","author":"Vlad","year":"2009","journal-title":"Cancer Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"5675","DOI":"10.1158\/1078-0432.CCR-13-1037","article-title":"CD62L as a therapeutic target in chronic lymphocytic leukemia","volume":"19","author":"Burgess","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1182\/blood-2015-02-626291","article-title":"L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo","volume":"126","author":"Lafouresse","year":"2015","journal-title":"Blood"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/0092-8674(90)90694-A","article-title":"CD44 is the principal cell surface receptor for hyaluronate","volume":"61","author":"Aruffo","year":"1990","journal-title":"Cell"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrm1004","article-title":"CD44: From adhesion molecules to signalling regulators","volume":"4","author":"Ponta","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"13841","DOI":"10.1073\/pnas.250484797","article-title":"A distinct glycoform of CD44 is an L-selectin ligand on human hematopoietic cells","volume":"97","author":"Dimitroff","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1083\/jcb.153.6.1277","article-title":"CD44 is a major E-selectin ligand on human hematopoietic progenitor cells","volume":"153","author":"Dimitroff","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"508","DOI":"10.4161\/cib.3.6.13495","article-title":"Multifaceted regulation of T cells by CD44","volume":"3","author":"Baaten","year":"2010","journal-title":"Commun. Integr. Biol."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Senbanjo, L.T., and Chellaiah, M.A. (2017). CD44: A Multifunctional Cell Surface Adhesion Receptor Is a Regulator of Progression and Metastasis of Cancer Cells. Front. Cell Dev. Biol., 5.","DOI":"10.3389\/fcell.2017.00018"},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Hassn Mesrati, M., Syafruddin, S.E., Mohtar, M.A., and Syahir, A. (2021). CD44: A Multifunctional Mediator of Cancer Progression. Biomolecules, 11.","DOI":"10.3390\/biom11121850"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13045-018-0605-5","article-title":"The biology and role of CD44 in cancer progression: Therapeutic implications","volume":"11","author":"Chen","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s11033-020-06094-y","article-title":"Alternative splicing modulates cancer aggressiveness: Role in EMT\/metastasis and chemoresistance","volume":"48","author":"Das","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1158\/0008-5472.CAN-12-2749","article-title":"CD40-mediated activation of chronic lymphocytic leukemia cells promotes their CD44-dependent adhesion to hyaluronan and restricts CCL21-induced motility","volume":"73","author":"Girbl","year":"2013","journal-title":"Cancer Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3389\/fimmu.2015.00177","article-title":"The Role of CD44 in the Pathophysiology of Chronic Lymphocytic Leukemia","volume":"6","author":"Gutjahr","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"156","DOI":"10.3389\/fimmu.2019.00156","article-title":"Molecular Players in Hematologic Tumor Cell Trafficking","volume":"10","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1182\/blood-2017-08-802462","article-title":"Microenvironment-induced CD44v6 promotes early disease progression in chronic lymphocytic leukemia","volume":"131","author":"Gutjahr","year":"2018","journal-title":"Blood"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"4126","DOI":"10.1182\/blood-2012-11-466250","article-title":"CD44 regulates the apoptotic response and promotes disease development in chronic lymphocytic leukemia","volume":"121","author":"Fedorchenko","year":"2013","journal-title":"Blood"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1093\/glycob\/cww026","article-title":"Fulfilling Koch\u2019s postulates in glycoscience: HCELL, GPS and translational glycobiology","volume":"26","author":"Sackstein","year":"2016","journal-title":"Glycobiology"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1182\/blood.V74.1.255.255","article-title":"Sialyl SSEA-1 antigen as a carbohydrate marker of human natural killer cells and immature lymphoid cells","volume":"74","author":"Ohmori","year":"1989","journal-title":"Blood"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.3324\/haematol.2022.281999","article-title":"Sialylation regulates migration in chronic lymphocytic leukemia","volume":"108","author":"Natoni","year":"2023","journal-title":"Haematologica"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"242","DOI":"10.3389\/fimmu.2012.00242","article-title":"Aspects of VLA-4 and LFA-1 regulation that may contribute to rolling and firm adhesion","volume":"3","author":"Chigaev","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1111\/j.1365-2141.2007.06965.x","article-title":"CD49d expression is an independent predictor of overall survival in patients with chronic lymphocytic leukaemia: A prognostic parameter with therapeutic potential","volume":"140","author":"Shanafelt","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1182\/blood-2007-05-092486","article-title":"Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia","volume":"111","author":"Gattei","year":"2008","journal-title":"Blood"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1038\/leu.2016.88","article-title":"CD49d prevails over the novel recurrent mutations as independent prognosticator of overall survival in chronic lymphocytic leukemia","volume":"30","author":"Bulian","year":"2016","journal-title":"Leukemia"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1200\/JCO.2013.50.8515","article-title":"CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia","volume":"32","author":"Bulian","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1182\/blood.2019003179","article-title":"CD49d promotes disease progression in chronic lymphocytic leukemia: New insights from CD49d bimodal expression","volume":"135","author":"Tissino","year":"2020","journal-title":"Blood"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"659","DOI":"10.2174\/1568009616666160809102219","article-title":"Functional and Clinical Significance of the Integrin Alpha Chain CD49d Expression in Chronic Lymphocytic Leukemia","volume":"16","author":"Tissino","year":"2016","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"4761","DOI":"10.4049\/jimmunol.0904149","article-title":"TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner","volume":"184","author":"Binsky","year":"2010","journal-title":"J. Immunol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"3121","DOI":"10.1158\/0008-5472.CAN-08-4136","article-title":"Circulating B-cell chronic lymphocytic leukemia cells display impaired migration to lymph nodes and bone marrow","volume":"69","author":"Hartmann","year":"2009","journal-title":"Cancer Res."},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Brachtl, G., Sahakyan, K., Denk, U., Girbl, T., Alinger, B., Hofbauer, S.W., Neureiter, D., Hofbauer, J.P., Egle, A., and Greil, R. (2011). Differential bone marrow homing capacity of VLA-4 and CD38 high expressing chronic lymphocytic leukemia cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023758"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1042\/BCJ20180415","article-title":"Regulation of cell migration by \u03b14 and \u03b19 integrins","volume":"476","author":"Parsons","year":"2019","journal-title":"Biochem. J."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1038\/sj.leu.2401602","article-title":"Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1)","volume":"13","author":"Failenschmid","year":"1999","journal-title":"Leukemia"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.leukres.2010.10.022","article-title":"CD49d is an independent prognostic marker that is associated with CXCR4 expression in CLL","volume":"35","author":"Majid","year":"2011","journal-title":"Leuk. Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1182\/blood.V99.8.2977","article-title":"The chemokine receptor CCR7 and \u03b14 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes","volume":"99","author":"Till","year":"2002","journal-title":"Blood"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"4813","DOI":"10.1182\/blood-2004-10-4054","article-title":"CLL, but not normal, B cells are dependent on autocrine VEGF and \u03b14\u03b21 integrin for chemokine-induced motility on and through endothelium","volume":"105","author":"Till","year":"2005","journal-title":"Blood"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/j.1365-2141.2004.04877.x","article-title":"The role of matrix metalloproteinase 9 in the pathogenesis of chronic lymphocytic leukaemia","volume":"125","author":"Kamiguti","year":"2004","journal-title":"Br. J. Haematol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1182\/blood-2006-03-007294","article-title":"MMP-9 in B-cell chronic lymphocytic leukemia is up-regulated by \u03b14\u03b21 integrin or CXCR4 engagement via distinct signaling pathways, localizes to podosomes, and is involved in cell invasion and migration","volume":"108","author":"Samaniego","year":"2006","journal-title":"Blood"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1182\/blood-2007-08-109249","article-title":"\u03b14\u03b21 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B\/MMP-9 in chronic leukemic but not in normal B cells","volume":"112","author":"Opdenakker","year":"2008","journal-title":"Blood"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"3317","DOI":"10.1182\/blood-2013-06-507335","article-title":"CD49d is overexpressed by trisomy 12 chronic lymphocytic leukemia cells: Evidence for a methylation-dependent regulation mechanism","volume":"122","author":"Zucchetto","year":"2013","journal-title":"Blood"},{"key":"ref_162","first-page":"212","article-title":"Evaluation of trisomy 12 by fluorescence in situ hybridization in peripheral blood, bone marrow and lymph nodes of patients with B-cell chronic lymphocytic leukemia","volume":"84","author":"Liso","year":"1999","journal-title":"Haematologica"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1038\/leu.2011.369","article-title":"The CD49d\/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells","volume":"26","author":"Zucchetto","year":"2012","journal-title":"Leukemia"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1111\/j.1365-2141.2011.08725.x","article-title":"Evidence for a macromolecular complex in poor prognosis CLL that contains CD38, CD49d, CD44 and MMP-9","volume":"154","author":"Buggins","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"254","DOI":"10.3389\/fimmu.2019.00254","article-title":"Beta2-Integrins and Interacting Proteins in Leukocyte Trafficking, Immune Suppression, and Immunodeficiency Disease","volume":"10","author":"Fagerholm","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.3109\/10428194.2013.867486","article-title":"Cell surface phenotype profiles distinguish stable and progressive chronic lymphocytic leukemia","volume":"55","author":"Huang","year":"2014","journal-title":"Leuk. Lymphoma"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0145-2126(96)00076-8","article-title":"Expression of adhesion molecules in 113 patients with B-cell chronic lymphocytic leukemia: Relationship with clinico-prognostic features","volume":"21","author":"Domingo","year":"1997","journal-title":"Leuk. Res."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1038\/sj.leu.2403975","article-title":"CD38 expression levels in chronic lymphocytic leukemia B cells are associated with activation marker expression and differential responses to interferon stimulation","volume":"19","author":"Pittner","year":"2005","journal-title":"Leukemia"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1111\/bjh.13188","article-title":"CD18 (ITGB2) expression in chronic lymphocytic leukaemia is regulated by DNA methylation-dependent and -independent mechanisms","volume":"169","author":"Hutterer","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1182\/blood-2016-02-697771","article-title":"Whole exome sequencing in families with CLL detects a variant in Integrin \u03b2 2 associated with disease susceptibility","volume":"128","author":"Goldin","year":"2016","journal-title":"Blood"},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"Nagy-Bal\u00f3, Z., Kiss, R., Demeter, J., B\u00f6d\u00f6r, C., Bajtay, Z., and Erdei, A. (2021). BCR activated CLL B cells use both CR3 (CD11b\/CD18) and CR4 (CD11c\/CD18) for adhesion while CR4 has a dominant role in migration towards SDF-1. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0254853"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.imlet.2017.05.016","article-title":"Functional studies of chronic lymphocytic leukemia B cells expressing \u03b2","volume":"189","author":"Uzonyi","year":"2017","journal-title":"Immunol. Lett."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1002\/hon.2927","article-title":"Nuclear \u03b1v\u03b23 integrin expression, post translational modifications and regulation in hematological malignancies","volume":"40","author":"Weisz","year":"2022","journal-title":"Hematol. Oncol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1038\/15233","article-title":"CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia","volume":"5","author":"Mateo","year":"1999","journal-title":"Nat. Med."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1002\/ddr.20265","article-title":"Integrin \u03b1v\u03b23-Targeted Cancer Therapy","volume":"69","author":"Liu","year":"2008","journal-title":"Drug Dev. Res."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"40943","DOI":"10.1074\/jbc.M111.231951","article-title":"Tyrosine phosphorylation as a conformational switch: A case study of integrin \u03b23 cytoplasmic tail","volume":"286","author":"Deshmukh","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1002\/jcp.20570","article-title":"A scoring system based on the expression of six surface molecules allows the identification of three prognostic risk groups in B-cell chronic lymphocytic leukemia","volume":"207","author":"Zucchetto","year":"2006","journal-title":"J. Cell. Physiol."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/hon.2947","article-title":"Elastin MIcrofibriL INterfacer1 (EMILIN-1) is an alternative prosurvival VLA-4 ligand in chronic lymphocytic leukemia","volume":"40","author":"Tissino","year":"2022","journal-title":"Hematol. Oncol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/sj.leu.2401275","article-title":"Fibronectin interaction with \u03b14\u03b21 integrin prevents apoptosis in B cell chronic lymphocytic leukemia: Correlation with Bcl-2 and Bax","volume":"13","author":"Casanova","year":"1999","journal-title":"Leukemia"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.bbrc.2003.10.054","article-title":"Involvement of p53 in \u03b14\u03b21 integrin-mediated resistance of B-CLL cells to fludarabine","volume":"311","author":"Casanova","year":"2003","journal-title":"Biochem. Biophys Res. Commun."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1182\/blood.V91.7.2387","article-title":"Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells","volume":"91","author":"Lagneaux","year":"1998","journal-title":"Blood"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1007\/s00277-018-3410-x","article-title":"In contrast to high CD49d, low CXCR4 expression indicates the dependency of chronic lymphocytic leukemia (CLL) cells on the microenvironment","volume":"97","author":"Kriston","year":"2018","journal-title":"Ann. Hematol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.ccr.2009.12.044","article-title":"Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain","volume":"17","author":"Terol","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1182\/bloodadvances.2019000019","article-title":"\u03b14\u03b21 integrin associates with VEGFR2 in CLL cells and contributes to VEGF binding and intracellular signaling","volume":"3","year":"2019","journal-title":"Blood Adv."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.3109\/10428194.2011.569962","article-title":"Activation of CD44, a receptor for extracellular matrix components, protects chronic lymphocytic leukemia cells from spontaneous and drug induced apoptosis through MCL-1","volume":"52","author":"Herishanu","year":"2011","journal-title":"Leuk. Lymphoma"},{"key":"ref_186","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_187","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_188","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.3324\/haematol.2020.262071","article-title":"Modulated expression of adhesion, migration and activation molecules may predict the degree of response in chronic lymphocytic leukemia patients treated with ibrutinib plus rituximab","volume":"106","author":"Peragine","year":"2020","journal-title":"Haematologica"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1080\/10428194.2022.2105324","article-title":"Early CD49d downmodulation in chronic lymphocytic leukemia patients treated front-line with ibrutinib plus rituximab predicts long-term response","volume":"63","author":"Peragine","year":"2022","journal-title":"Leuk. Lymphoma"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1182\/blood-2011-05-352492","article-title":"The phosphoinositide 3\u2032-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia","volume":"118","author":"Hoellenriegel","year":"2011","journal-title":"Blood"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1182\/blood-2009-08-236471","article-title":"Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia","volume":"115","author":"Friedberg","year":"2010","journal-title":"Blood"},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/S1470-2045(13)70513-8","article-title":"Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: An open-label, multicentre, phase 1b\/2 trial","volume":"15","author":"Furman","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.1182\/blood-2011-11-390989","article-title":"The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia","volume":"119","author":"Kuil","year":"2012","journal-title":"Blood"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1084\/jem.20171288","article-title":"Functional and clinical relevance of VLA-4 (CD49d\/CD29) in ibrutinib-treated chronic lymphocytic leukemia","volume":"215","author":"Tissino","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"3612","DOI":"10.1158\/1078-0432.CCR-22-3217","article-title":"CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy","volume":"29","author":"Alsadhan","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"35123","DOI":"10.18632\/oncotarget.26212","article-title":"CXCR4- and BCR-triggered integrin activation in B-cell chronic lymphocytic leukemia cells depends on JAK2-activated Bruton\u2019s tyrosine kinase","volume":"9","author":"Montresor","year":"2018","journal-title":"Oncotarget"},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/leu.2015.316","article-title":"BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia","volume":"30","author":"Chen","year":"2016","journal-title":"Leukemia"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1158\/1078-0432.CCR-15-0781","article-title":"Treatment with Ibrutinib Inhibits BTK- and VLA-4-Dependent Adhesion of Chronic Lymphocytic Leukemia Cells In Vivo","volume":"21","author":"Herman","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/sj.leu.2401621","article-title":"Role of beta2 integrins in the prevention of apoptosis induction in chronic lymphocytic leukemia B cells","volume":"14","author":"Plate","year":"2000","journal-title":"Leukemia"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/21\/5160\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:12:24Z","timestamp":1760130744000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/21\/5160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,26]]},"references-count":199,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["cancers15215160"],"URL":"https:\/\/doi.org\/10.3390\/cancers15215160","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,26]]}}}