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This notion was initially suggested by observations of the CLL BcR repertoire and of correlations existing between certain BcR features and the clinical outcomes of single patients. Based on these observations, tyrosine kinase inhibitors (TKIs), which block BcR signaling, have been introduced in therapy with the aim of inhibiting CLL cell clonal expansion and of controlling the disease. Indeed, the impressive results obtained with these compounds provided further proof of the role of BcR in CLL. In this article, the key steps that led to the determination of the role of BcR are reviewed, including the features of the CLL cell repertoire and the fine mechanisms causing BcR engagement and cell signaling. Furthermore, we discuss the biological effects of the engagement, which can lead to cell survival\/proliferation or apoptosis depending on certain intrinsic cell characteristics and on signals that the micro-environment can deliver to the leukemic cells. In addition, consideration is given to alternative mechanisms promoting cell proliferation in the absence of BcR signaling, which can explain in part the incomplete effectiveness of TKI therapies. The role of the BcR in determining clonal evolution and disease progression is also described. Finally, we discuss possible models to explain the selection of a special BcR set during leukemogenesis. The BcR may deliver activation signals to the cells, which lead to their uncontrolled growth, with the possible collaboration of other still-undefined events which are capable of deregulating the normal physiological response of B cells to BcR-delivered stimuli.<\/jats:p>","DOI":"10.3390\/ijms232214249","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T03:29:50Z","timestamp":1668742190000},"page":"14249","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Old and New Facts and Speculations on the Role of the B Cell Receptor in the Origin of Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"23","author":[{"given":"Davide","family":"Bagnara","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Nicola","family":"Mazzarello","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Ghiotto","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy"},{"name":"IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5512-8106","authenticated-orcid":false,"given":"Monica","family":"Colombo","sequence":"additional","affiliation":[{"name":"IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3335-1101","authenticated-orcid":false,"given":"Giovanna","family":"Cutrona","sequence":"additional","affiliation":[{"name":"IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6643-7083","authenticated-orcid":false,"given":"Franco","family":"Fais","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy"},{"name":"IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manlio","family":"Ferrarini","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1056\/NEJMra041720","article-title":"Chronic Lymphocytic Leukemia","volume":"352","author":"Chiorazzi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1056\/NEJMra1908213","article-title":"Treatment of Chronic Lymphocytic Leukemia","volume":"383","author":"Burger","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1182\/blood.2020010029","article-title":"Exploring the Pathways to Chronic Lymphocytic Leukemia","volume":"138","author":"Stevenson","year":"2021","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1002\/ajh.25595","article-title":"Chronic Lymphocytic Leukemia: 2020 Update on Diagnosis, Risk Stratification and Treatment","volume":"94","author":"Hallek","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/ajh.24282","article-title":"Chronic Lymphocytic Leukemia (CLL)-Then and Now","volume":"91","author":"Rai","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1182\/blood.V94.6.1840","article-title":"Ig V Gene Mutation Status and CD38 Expression as Novel Prognostic Indicators in Chronic Lymphocytic Leukemia","volume":"94","author":"Damle","year":"1999","journal-title":"Blood"},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"S566","DOI":"10.1182\/blood.V29.4.566.566","article-title":"Chronic Lymphocytic Leukemia\u2014An Accumulative Disease of Immunolgically Incompetent Lymphocytes","volume":"29","author":"Dameshek","year":"1967","journal-title":"Blood"},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1038\/leu.2017.34","article-title":"Leukemia-Cell Proliferation and Disease Progression in Patients with Early Stage Chronic Lymphocytic Leukemia","volume":"31","author":"Murphy","year":"2017","journal-title":"Leukemia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/978-1-4939-8876-1_11","article-title":"Measurement of Leukemic B-Cell Growth Kinetics in Patients with Chronic Lymphocytic Leukemia","volume":"1881","author":"Mazzarello","year":"2019","journal-title":"Methods Mol. Biol. Clifton N. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1182\/blood-2012-02-409110","article-title":"T-Cell Independent, B-Cell Receptor-Mediated Induction of Telomerase Activity Differs among IGHV Mutation-Based Subgroups of Chronic Lymphocytic Leukemia Patients","volume":"120","author":"Damle","year":"2012","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"612665","DOI":"10.3389\/fonc.2020.612665","article-title":"Telomere Dysfunction in Chronic Lymphocytic Leukemia","volume":"10","author":"Jebaraj","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1056\/NEJM199911113412007","article-title":"Cellular Origin of Human B-Cell Lymphomas","volume":"341","author":"Klein","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1182\/blood.V77.7.1516.1516","article-title":"Patterns of Chromosomal Breakpoint Locations in Burkitt\u2019s Lymphoma: Relevance to Geography and Epstein-Barr Virus Association","volume":"77","author":"Shiramizu","year":"1991","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5580","DOI":"10.1038\/sj.onc.1204640","article-title":"Mechanisms of Chromosomal Translocations in B Cell Lymphomas","volume":"20","year":"2001","journal-title":"Oncogene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/s41572-019-0132-x","article-title":"Follicular Lymphoma","volume":"5","author":"Carbone","year":"2019","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/cdd.2017.159","article-title":"BCL2 and MiR-15\/16: From Gene Discovery to Treatment","volume":"25","author":"Pekarsky","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1910","DOI":"10.1056\/NEJM200012283432602","article-title":"Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia","volume":"343","author":"Stilgenbauer","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/s41375-017-0007-7","article-title":"ERIC Recommendations for TP53 Mutation Analysis in Chronic Lymphocytic Leukemia-Update on Methodological Approaches and Results Interpretation","volume":"32","author":"Malcikova","year":"2018","journal-title":"Leukemia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/978-1-4939-8876-1_6","article-title":"Detection and Functional Analysis of TP53 Mutations in CLL","volume":"1881","author":"Pavlova","year":"2019","journal-title":"Methods Mol. Biol. Clifton N. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/17474086.2019.1575130","article-title":"Genetic Mutations in Chronic Lymphocytic Leukemia: Impact on Clinical Treatment","volume":"12","author":"Condoluci","year":"2019","journal-title":"Expert Rev. Hematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1182\/blood-2015-07-659144","article-title":"Clinical Impact of Clonal and Subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM Mutations in Chronic Lymphocytic Leukemia","volume":"127","author":"Nadeu","year":"2016","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/nrc.2016.8","article-title":"The Molecular Pathogenesis of Chronic Lymphocytic Leukaemia","volume":"16","author":"Fabbri","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/j.1365-2141.2005.05550.x","article-title":"International Familial CLL Consortium Diagnostic Criteria for Monoclonal B-Cell Lymphocytosis","volume":"130","author":"Marti","year":"2005","journal-title":"Br. J. Haematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1182\/blood-2015-02-585059","article-title":"Monoclonal B-Cell Lymphocytosis and Early-Stage Chronic Lymphocytic Leukemia: Diagnosis, Natural History, and Risk Stratification","volume":"126","author":"Strati","year":"2015","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.semcancer.2013.08.003","article-title":"Monoclonal B Cell Lymphocytosis and \u201cin Situ\u201d Lymphoma","volume":"24","author":"Karube","year":"2014","journal-title":"Semin. Cancer Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1182\/blood-2009-01-197368","article-title":"Increased Frequency (12%) of Circulating Chronic Lymphocytic Leukemia-like B-Cell Clones in Healthy Subjects Using a Highly Sensitive Multicolor Flow Cytometry Approach","volume":"114","author":"Nieto","year":"2009","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6618","DOI":"10.1182\/blood-2011-05-357251","article-title":"General Population Low-Count CLL-like MBL Persists over Time without Clinical Progression, Although Carrying the Same Cytogenetic Abnormalities of CLL","volume":"118","author":"Fazi","year":"2011","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e334","DOI":"10.1016\/S2352-3026(16)30192-2","article-title":"Monoclonal B-Cell Lymphocytosis in a Hospital-Based UK Population and a Rural Ugandan Population: A Cross-Sectional Study","volume":"4","author":"Rawstron","year":"2017","journal-title":"Lancet Haematol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1097\/MOH.0b013e328338cd99","article-title":"Familial Chronic Lymphocytic Leukemia","volume":"17","author":"Goldin","year":"2010","journal-title":"Curr. Opin. Hematol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1182\/blood-2012-03-413591","article-title":"Common Variation at 6p21.31 (BAK1) Influences the Risk of Chronic Lymphocytic Leukemia","volume":"120","author":"Slager","year":"2012","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ng.510","article-title":"Common Variants at 2q37.3, 8q24.21, 15q21.3, and 16q24.1 Influence Chronic Lymphocytic Leukemia Risk","volume":"42","author":"Broderick","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1038\/ng.219","article-title":"A Genome-Wide Association Study Identifies Six Susceptibility Loci for Chronic Lymphocytic Leukemia","volume":"40","author":"Broderick","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1182\/blood-2004-01-0341","article-title":"Familial Risk of Lymphoproliferative Tumors in Families of Patients with Chronic Lymphocytic Leukemia: Results from the Swedish Family-Cancer Database","volume":"104","author":"Goldin","year":"2004","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1146\/annurev.immunol.21.120601.141018","article-title":"B Cell Chronic Lymphocytic Leukemia: Lessons Learned from Studies of the B Cell Antigen Receptor","volume":"21","author":"Chiorazzi","year":"2003","journal-title":"Annu. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1084\/jem.169.1.255","article-title":"Production of Autoantibodies by CD5-Expressing B Lymphocytes from Patients with Chronic Lymphocytic Leukemia","volume":"169","author":"Sthoeger","year":"1989","journal-title":"J. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1182\/blood.V76.3.562.562","article-title":"Evidence That Chronic Lymphocytic Leukemia B Lymphocytes Are Frequently Committed to Production of Natural Autoantibodies","volume":"76","author":"Borche","year":"1990","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1084\/jem.20121801","article-title":"A Mutated B Cell Chronic Lymphocytic Leukemia Subset That Recognizes and Responds to Fungi","volume":"210","author":"Hoogeboom","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/nrc.2017.121","article-title":"Targeting B Cell Receptor Signalling in Cancer: Preclinical and Clinical Advances","volume":"18","author":"Burger","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1172\/JCI3009","article-title":"Chronic Lymphocytic Leukemia B Cells Express Restricted Sets of Mutated and Unmutated Antigen Receptors","volume":"102","author":"Fais","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/0167-5699(94)90009-4","article-title":"The Pathogenesis of Chronic Lymphocytic Leukemia: Analysis of the Antibody Repertoire","volume":"15","author":"Schroeder","year":"1994","journal-title":"Immunol. Today"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"235","DOI":"10.4049\/jimmunol.158.1.235","article-title":"Ig VH1 Genes Expressed in B Cell Chronic Lymphocytic Leukemia Exhibit Distinctive Molecular Features","volume":"158","author":"Johnson","year":"1997","journal-title":"J. Immunol. Baltim."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3575","DOI":"10.1182\/blood-2005-04-1511","article-title":"Immunoglobulin Light Chain Repertoire in Chronic Lymphocytic Leukemia","volume":"106","author":"Stamatopoulos","year":"2005","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"95","DOI":"10.4049\/jimmunol.166.1.95","article-title":"Normal B Cells Express 51p1-Encoded Ig Heavy Chains That Are Distinct from Those Expressed by Chronic Lymphocytic Leukemia B Cells","volume":"166","author":"Widhopf","year":"2001","journal-title":"J. Immunol. Baltim."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Hwang, K.-K., Trama, A.M., Kozink, D.M., Chen, X., Wiehe, K., Cooper, A.J., Xia, S.-M., Wang, M., Marshall, D.J., and Whitesides, J. (2014). IGHV1-69 B Cell Chronic Lymphocytic Leukemia Antibodies Cross-React with HIV-1 and Hepatitis C Virus Antigens as Well as Intestinal Commensal Bacteria. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090725"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1046\/j.1365-2567.1998.00406.x","article-title":"Human Monoclonal Antibodies Encoded by the V4-34 Gene Segment Show Cold Agglutinin Activity and Variable Multireactivity Which Correlates with the Predicted Charge of the Heavy-Chain Variable Region","volume":"93","author":"Thorpe","year":"1998","journal-title":"Immunology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1182\/blood-2017-09-805762","article-title":"Biased IGH VDJ Gene Repertoire and Clonal Expansions in B Cells of Chronically Hepatitis C Virus-Infected Individuals","volume":"131","author":"Tucci","year":"2018","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1182\/blood-2011-08-375501","article-title":"The IGHV1-69\/IGHJ3 Recombinations of Unmutated CLL Are Distinct from Those of Normal B Cells","volume":"119","author":"Forconi","year":"2012","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1172\/JCI19399","article-title":"Remarkably Similar Antigen Receptors among a Subset of Patients with Chronic Lymphocytic Leukemia","volume":"113","author":"Ghiotto","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1182\/blood-2004-03-0818","article-title":"Chronic Lymphocytic Leukemia B Cells of More than 1% of Patients Express Virtually Identical Immunoglobulins","volume":"104","author":"Widhopf","year":"2004","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1084\/jem.20040544","article-title":"Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia","volume":"200","author":"Messmer","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2879","DOI":"10.1182\/blood-2004-01-0132","article-title":"Subsets with Restricted Immunoglobulin Gene Rearrangement Features Indicate a Role for Antigen Selection in the Development of Chronic Lymphocytic Leukemia","volume":"104","author":"Tobin","year":"2004","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2889","DOI":"10.1182\/blood-2005-06-2227","article-title":"Strikingly Homologous Immunoglobulin Gene Rearrangements and Poor Outcome in VH3-21-Using Chronic Lymphocytic Leukemia Patients Independent of Geographic Origin and Mutational Status","volume":"107","author":"Murray","year":"2006","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1182\/blood-2006-03-012948","article-title":"Over 20% of Patients with Chronic Lymphocytic Leukemia Carry Stereotyped Receptors: Pathogenetic Implications and Clinical Correlations","volume":"109","author":"Stamatopoulos","year":"2007","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1182\/blood.2020007039","article-title":"Higher-Order Connections between Stereotyped Subsets: Implications for Improved Patient Classification in CLL","volume":"137","author":"Agathangelidis","year":"2021","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.1182\/blood-2011-11-393694","article-title":"Stereotyped B-Cell Receptors in One-Third of Chronic Lymphocytic Leukemia: A Molecular Classification with Implications for Targeted Therapies","volume":"119","author":"Agathangelidis","year":"2012","journal-title":"Blood"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5771","DOI":"10.4049\/jimmunol.1300321","article-title":"Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability","volume":"190","author":"Marcatili","year":"2013","journal-title":"J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1084\/jem.178.4.1419","article-title":"Molecular Characterization of a Cross-Reactive Idiotope on Human Immunoglobulins Utilizing the VH4-21 Gene Segment","volume":"178","author":"Potter","year":"1993","journal-title":"J. Exp. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41586-020-2262-4","article-title":"BCR Selection and Affinity Maturation in Peyer\u2019s Patch Germinal Centres","volume":"582","author":"Chen","year":"2020","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1038\/leu.2017.125","article-title":"Immunoglobulin Gene Sequence Analysis in Chronic Lymphocytic Leukemia: Updated ERIC Recommendations","volume":"31","author":"Rosenquist","year":"2017","journal-title":"Leukemia"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5292","DOI":"10.1158\/1078-0432.CCR-16-3100","article-title":"Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes","volume":"23","author":"Xochelli","year":"2017","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41375-018-0303-x","article-title":"The Importance of B Cell Receptor Isotypes and Stereotypes in Chronic Lymphocytic Leukemia","volume":"33","author":"Gounari","year":"2019","journal-title":"Leukemia"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1182\/blood.2019003453","article-title":"International Prognostic Score for Asymptomatic Early-Stage Chronic Lymphocytic Leukemia","volume":"135","author":"Condoluci","year":"2020","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1182\/blood.2020006322","article-title":"Natural History of Monoclonal B-Cell Lymphocytosis among Relatives in CLL Families","volume":"137","author":"Slager","year":"2021","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1182\/blood.2021012890","article-title":"High-Risk Subtypes of Chronic Lymphocytic Leukemia Are Detectable as Early as 16 Years Prior to Diagnosis","volume":"139","author":"Kolijn","year":"2022","journal-title":"Blood"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Henriques, A., Rodr\u00edguez-Caballero, A., Nieto, W.G., Langerak, A.W., Criado, I., L\u00e9crevisse, Q., Gonz\u00e1lez, M., Pais, M.L., Paiva, A., and Almeida, J. (2013). Combined Patterns of IGHV Repertoire and Cytogenetic\/Molecular Alterations in Monoclonal B Lymphocytosis versus Chronic Lymphocytic Leukemia. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0067751"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/j.1365-2141.2009.07711.x","article-title":"The Prognosis of Clinical Monoclonal B Cell Lymphocytosis Differs from Prognosis of Rai 0 Chronic Lymphocytic Leukaemia and Is Recapitulated by Biological Risk Factors","volume":"146","author":"Rossi","year":"2009","journal-title":"Br. J. Haematol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5890","DOI":"10.1158\/1078-0432.CCR-13-0622","article-title":"Clinical Monoclonal B Lymphocytosis versus Rai 0 Chronic Lymphocytic Leukemia: A Comparison of Cellular, Cytogenetic, Molecular, and Clinical Features","volume":"19","author":"Morabito","year":"2013","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1182\/blood-2008-09-176933","article-title":"The Immunoglobulin Gene Repertoire of Low-Count Chronic Lymphocytic Leukemia (CLL)-like Monoclonal B Lymphocytosis Is Different from CLL: Diagnostic Implications for Clinical Monitoring","volume":"114","author":"Dagklis","year":"2009","journal-title":"Blood"},{"key":"ref_71","first-page":"25","article-title":"Tracing CLL-Biased Stereotyped Immunoglobulin Gene Rearrangements in Normal B Cell Subsets Using a High-Throughput Immunogenetic Approach","volume":"26","author":"Colombo","year":"2020","journal-title":"Mol. Med. Camb. Mass"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"894419","DOI":"10.3389\/fonc.2022.894419","article-title":"Characterizing Features of Human Circulating B Cells Carrying CLL-Like Stereotyped Immunoglobulin Rearrangements","volume":"12","author":"Bagnara","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1084\/jem.155.2.623","article-title":"Infrequent Normal B Lymphocytes Express Features of B-Chronic Lymphocytic Leukemia","volume":"155","author":"Gobbi","year":"1982","journal-title":"J. Exp. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1084\/jem.151.6.1539","article-title":"Identification of a P69,71 Complex Expressed on Human T Cells Sharing Determinants with B-Type Chronic Lymphatic Leukemic Cells","volume":"151","author":"Wang","year":"1980","journal-title":"J. Exp. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.1002\/eji.201445146","article-title":"Perspectives on Fetal Derived CD5+ B1 B Cells","volume":"45","author":"Hardy","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1182\/blood-2010-07-155663","article-title":"Cellular Origin(s) of Chronic Lymphocytic Leukemia: Cautionary Notes and Additional Considerations and Possibilities","volume":"117","author":"Chiorazzi","year":"2011","journal-title":"Blood"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1084\/jem.20120833","article-title":"Cellular Origin and Pathophysiology of Chronic Lymphocytic Leukemia","volume":"209","author":"Seifert","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1056\/NEJMra1804280","article-title":"Clinical and Therapeutic Implications of Cancer Stem Cells","volume":"380","author":"Clarke","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/nrc1409","article-title":"MALT Lymphoma: From Morphology to Molecules","volume":"4","author":"Isaacson","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4838","DOI":"10.1182\/blood-2012-01-404194","article-title":"Helicobacter pylori Eradication Therapy Is Effective in the Treatment of Early-Stage H pylori-Positive Gastric Diffuse Large B-Cell Lymphomas","volume":"119","author":"Kuo","year":"2012","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.1182\/blood.V98.13.3745","article-title":"The B-Cell Receptor of a Hepatitis C Virus (HCV)-Associated Non-Hodgkin Lymphoma Binds the Viral E2 Envelope Protein, Implicating HCV in Lymphomagenesis","volume":"98","author":"Quinn","year":"2001","journal-title":"Blood"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1056\/NEJMoa013376","article-title":"Regression of Splenic Lymphoma with Villous Lymphocytes after Treatment of Hepatitis C Virus Infection","volume":"347","author":"Hermine","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/nrd3937","article-title":"Targeting Pathological B Cell Receptor Signalling in Lymphoid Malignancies","volume":"12","author":"Young","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/S0092-8674(00)80373-6","article-title":"In Vivo Ablation of Surface Immunoglobulin on Mature B Cells by Inducible Gene Targeting Results in Rapid Cell Death","volume":"90","author":"Lam","year":"1997","journal-title":"Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.cell.2004.05.014","article-title":"Survival of Resting Mature B Lymphocytes Depends on BCR Signaling via the Igalpha\/Beta Heterodimer","volume":"117","author":"Kraus","year":"2004","journal-title":"Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nature09357","article-title":"Oligomeric Organization of the B-Cell Antigen Receptor on Resting Cells","volume":"467","author":"Yang","year":"2010","journal-title":"Nature"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4872","DOI":"10.1016\/j.febslet.2010.09.045","article-title":"The Dissociation Activation Model of B Cell Antigen Receptor Triggering","volume":"584","author":"Yang","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.cell.2009.08.041","article-title":"PI3 Kinase Signals BCR-Dependent Mature B Cell Survival","volume":"139","author":"Srinivasan","year":"2009","journal-title":"Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1172\/JCI118961","article-title":"Examples of in Vivo Isotype Class Switching in IgM+ Chronic Lymphocytic Leukemia B Cells","volume":"98","author":"Fais","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1182\/blood.V87.4.1586.bloodjournal8741586","article-title":"Evidence for Progenitors of Chronic Lymphocytic Leukemia B Cells That Undergo Intraclonal Differentiation and Diversification","volume":"87","author":"Dono","year":"1996","journal-title":"Blood"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1038\/s41467-019-08677-1","article-title":"Differential Organization of Tonic and Chronic B Cell Antigen Receptors in the Plasma Membrane","volume":"10","author":"Wildhagen","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1182\/blood.V14.10.1151.1151","article-title":"Leukemia and Auto-Immunization\u2014Some Possible Relationships","volume":"14","author":"Dameshek","year":"1959","journal-title":"Blood"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1172\/JCI24387","article-title":"Unmutated and Mutated Chronic Lymphocytic Leukemias Derive from Self-Reactive B Cell Precursors despite Expressing Different Antibody Reactivity","volume":"115","author":"Xu","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.leukres.2016.09.002","article-title":"Autoimmune Hemolytic Anemia (AIHA) Associated with Chronic Lymphocytic Leukemia in the Current Era of Targeted Therapy","volume":"50","author":"Molica","year":"2016","journal-title":"Leuk. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/j.1365-2141.1989.tb07643.x","article-title":"Identification of Normal B-Cell Counterparts of Neoplastic Cells Which Secrete Cold Agglutinins of Anti-I and Anti-i Specificity","volume":"72","author":"Stevenson","year":"1989","journal-title":"Br. J. Haematol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1182\/blood.V62.2.495.495","article-title":"Differentiation of Chronic Lymphocytic Leukemia Cells: Correlation between the Synthesis and Secretion of Immunoglobulins and the Ultrastructure of the Malignant Cells","volume":"62","author":"Rubartelli","year":"1983","journal-title":"Blood"},{"key":"ref_97","first-page":"665","article-title":"Chronic Lymphocytic Leukemia Cells Recognize Conserved Epitopes Associated with Apoptosis and Oxidation","volume":"14","author":"Catera","year":"2008","journal-title":"Mol. Med. Camb. Mass"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3907","DOI":"10.1182\/blood-2009-09-244251","article-title":"Many Chronic Lymphocytic Leukemia Antibodies Recognize Apoptotic Cells with Exposed Nonmuscle Myosin Heavy Chain IIA: Implications for Patient Outcome and Cell of Origin","volume":"115","author":"Chu","year":"2010","journal-title":"Blood"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3838","DOI":"10.1182\/blood-2007-11-125450","article-title":"A New Perspective: Molecular Motifs on Oxidized LDL, Apoptotic Cells, and Bacteria Are Targets for Chronic Lymphocytic Leukemia Antibodies","volume":"111","author":"Hellqvist","year":"2008","journal-title":"Blood"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.molimm.2004.07.045","article-title":"The Role of IgM Antibodies in the Recognition and Clearance of Apoptotic Cells","volume":"42","author":"Peng","year":"2005","journal-title":"Mol. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nature11309","article-title":"Chronic Lymphocytic Leukaemia Is Driven by Antigen-Independent Cell-Autonomous Signalling","volume":"489","author":"Schneider","year":"2012","journal-title":"Nature"},{"key":"ref_102","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_103","first-page":"E1500","article-title":"Autoantigen Can Promote Progression to a More Aggressive TCL1 Leukemia by Selecting Variants with Enhanced B-Cell Receptor Signaling","volume":"110","author":"Chen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1038\/nm.3388","article-title":"The Quest to Overcome Resistance to EGFR-Targeted Therapies in Cancer","volume":"19","author":"Chong","year":"2013","journal-title":"Nat. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/nrc2780","article-title":"Fibroblast Growth Factor Signalling: From Development to Cancer","volume":"10","author":"Turner","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1182\/blood-2012-09-454439","article-title":"CLL B-Cell Receptors Can Recognize Themselves: Alternative Epitopes and Structural Clues for Autostimulatory Mechanisms in CLL","volume":"121","author":"Binder","year":"2013","journal-title":"Blood"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"4320","DOI":"10.1073\/pnas.1913810117","article-title":"IGLV3-21*01 Is an Inherited Risk Factor for CLL through the Acquisition of a Single-Point Mutation Enabling Autonomous BCR Signaling","volume":"117","author":"Maity","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1053\/j.semdp.2011.02.014","article-title":"Chronic Lymphocytic Leukemia: The Pathologist\u2019s View of Lymph Node Microenvironment","volume":"28","author":"Ponzoni","year":"2011","journal-title":"Semin. Diagn. Pathol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"E216","DOI":"10.1002\/ajh.25206","article-title":"Immunoglobulin Heavy Chain Variable Region Gene and Prediction of Time to First Treatment in Patients with Chronic Lymphocytic Leukemia: Mutational Load or Mutational Status? Analysis of 1003 Cases","volume":"93","author":"Morabito","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"897280","DOI":"10.3389\/fonc.2022.897280","article-title":"Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients with Chronic Lymphocytic Leukemia","volume":"12","author":"Kaufman","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"15746","DOI":"10.1038\/ncomms15746","article-title":"Distinct Homotypic B-Cell Receptor Interactions Shape the Outcome of Chronic Lymphocytic Leukaemia","volume":"8","author":"Minici","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"4087","DOI":"10.1182\/blood.V99.11.4087","article-title":"B-Cell Chronic Lymphocytic Leukemia Cells Express a Surface Membrane Phenotype of Activated, Antigen-Experienced B Lymphocytes","volume":"99","author":"Damle","year":"2002","journal-title":"Blood"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.it.2013.07.002","article-title":"B Cell Receptor Signaling in Chronic Lymphocytic Leukemia","volume":"34","author":"Burger","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1182\/blood.V88.4.1365.bloodjournal8841365","article-title":"CD38 Expression Distinguishes Two Groups of B-Cell Chronic Lymphocytic Leukemias with Different Responses to Anti-IgM Antibodies and Propensity to Apoptosis","volume":"88","author":"Zupo","year":"1996","journal-title":"Blood"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3470","DOI":"10.1182\/blood-2011-06-275610","article-title":"CD38 and Chronic Lymphocytic Leukemia: A Decade Later","volume":"118","author":"Malavasi","year":"2011","journal-title":"Blood"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"4609","DOI":"10.1182\/blood-2002-06-1683","article-title":"Expression of ZAP-70 Is Associated with Increased B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia","volume":"100","author":"Chen","year":"2002","journal-title":"Blood"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1182\/blood-2002-06-1822","article-title":"Differential Signaling via Surface IgM Is Associated with VH Gene Mutational Status and CD38 Expression in Chronic Lymphocytic Leukemia","volume":"101","author":"Lanham","year":"2003","journal-title":"Blood"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"413","DOI":"10.3324\/haematol.11646","article-title":"Clonal Heterogeneity in Chronic Lymphocytic Leukemia Cells: Superior Response to Surface IgM Cross-Linking in CD38, ZAP-70-Positive Cells","volume":"93","author":"Cutrona","year":"2008","journal-title":"Haematologica"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1182\/blood-2007-04-083832","article-title":"CD38 Expression Labels an Activated Subset within Chronic Lymphocytic Leukemia Clones Enriched in Proliferating B Cells","volume":"110","author":"Damle","year":"2007","journal-title":"Blood"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"4832","DOI":"10.1182\/blood-2009-05-219634","article-title":"In Vivo Intraclonal and Interclonal Kinetic Heterogeneity in B-Cell Chronic Lymphocytic Leukemia","volume":"114","author":"Calissano","year":"2009","journal-title":"Blood"},{"key":"ref_121","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_122","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-KappaB Activation, and Tumor Proliferation in Chronic Lymphocytic Leukemia","volume":"117","author":"Herishanu","year":"2011","journal-title":"Blood"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"3163","DOI":"10.1038\/s41375-021-01249-7","article-title":"Myeloid-Derived Suppressor Cell Subtypes Differentially Influence T-Cell Function, T-Helper Subset Differentiation, and Clinical Course in CLL","volume":"35","author":"Ferrer","year":"2021","journal-title":"Leukemia"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1182\/blood-2005-08-3182","article-title":"CXCR4: A Key Receptor in the Crosstalk between Tumor Cells and Their Microenvironment","volume":"107","author":"Burger","year":"2006","journal-title":"Blood"},{"key":"ref_125","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_126","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1182\/blood-2010-04-282400","article-title":"Chronic Lymphocytic Leukemia Cells Receive RAF-Dependent Survival Signals in Response to CXCL12 That Are Sensitive to Inhibition by Sorafenib","volume":"117","author":"Messmer","year":"2011","journal-title":"Blood"},{"key":"ref_127","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_128","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/JLB.MR0618-226R","article-title":"The Multiple Faces of CD5","volume":"105","author":"Soldevila","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_129","first-page":"1374","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. Camb. Mass"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1182\/bloodadvances.2019000817","article-title":"CLL Intraclonal Fractions Exhibit Established and Recently Acquired Patterns of DNA Methylation","volume":"4","author":"Bartholdy","year":"2020","journal-title":"Blood Adv."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1182\/blood-2014-03-559690","article-title":"MicroRNA-155 Influences B-Cell Receptor Signaling and Associates with Aggressive Disease in Chronic Lymphocytic Leukemia","volume":"124","author":"Cui","year":"2014","journal-title":"Blood"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1182\/blood-2016-03-707786","article-title":"Surface IgM Expression and Function Are Associated with Clinical Behavior, Genetic Abnormalities, and DNA Methylation in CLL","volume":"128","author":"Drennan","year":"2016","journal-title":"Blood"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.autrev.2007.02.021","article-title":"Signaling Pathways Activated by Antigen-Receptor Engagement in Chronic Lymphocytic Leukemia B-Cells","volume":"7","author":"Efremov","year":"2007","journal-title":"Autoimmun. Rev."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1182\/blood-2007-12-127688","article-title":"BCR Ligation Induced by IgM Stimulation Results in Gene Expression and Functional Changes Only in IgV H Unmutated Chronic Lymphocytic Leukemia (CLL) Cells","volume":"112","author":"Guarini","year":"2008","journal-title":"Blood"},{"key":"ref_135","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_136","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_137","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_138","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_139","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_140","doi-asserted-by":"crossref","first-page":"15524","DOI":"10.1073\/pnas.242606799","article-title":"Frequent Deletions and Down-Regulation of Micro- RNA Genes MiR15 and MiR16 at 13q14 in Chronic Lymphocytic Leukemia","volume":"99","author":"Calin","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.ccr.2009.11.019","article-title":"The DLEU2\/MiR-15a\/16-1 Cluster Controls B Cell Proliferation and Its Deletion Leads to Chronic Lymphocytic Leukemia","volume":"17","author":"Klein","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"13944","DOI":"10.1073\/pnas.0506654102","article-title":"MiR-15 and MiR-16 Induce Apoptosis by Targeting BCL2","volume":"102","author":"Cimmino","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1038\/leu.2016.394","article-title":"Effects of MiRNA-15 and MiRNA-16 Expression Replacement in Chronic Lymphocytic Leukemia: Implication for Therapy","volume":"31","author":"Cutrona","year":"2017","journal-title":"Leukemia"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1182\/hematology.2020000154","article-title":"Therapeutic Development and Current Uses of BCL-2 Inhibition","volume":"2020","author":"Roberts","year":"2020","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1056\/NEJMoa1815281","article-title":"Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions","volume":"380","author":"Fischer","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1038\/leu.2012.98","article-title":"N-(4-Hydroxyphenyl)Retinamide Promotes Apoptosis of Resting and Proliferating B-Cell Chronic Lymphocytic Leukemia Cells and Potentiates Fludarabine and ABT-737 Cytotoxicity","volume":"26","author":"Bruno","year":"2012","journal-title":"Leukemia"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/cyto.a.20819","article-title":"BH3-Only Proteins: The Death-Puppeteer\u2019s Wires","volume":"77","author":"Ghiotto","year":"2010","journal-title":"Cytom. Part J. Int. Soc. Anal. Cytol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1182\/blood-2015-07-660969","article-title":"Engagement of the B-Cell Receptor of Chronic Lymphocytic Leukemia Cells Drives Global and MYC-Specific MRNA Translation","volume":"127","author":"Yeomans","year":"2016","journal-title":"Blood"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/s41375-021-01381-4","article-title":"Longitudinal Analyses of CLL in Mice Identify Leukemia-Related Clonal Changes Including a Myc Gain Predicting Poor Outcome in Patients","volume":"36","author":"Paul","year":"2022","journal-title":"Leukemia"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"6117","DOI":"10.1158\/0008-5472.CAN-21-1273","article-title":"Activation of Notch and Myc Signaling via B-Cell-Restricted Depletion of Dnmt3a Generates a Consistent Murine Model of Chronic Lymphocytic Leukemia","volume":"81","author":"Biran","year":"2021","journal-title":"Cancer Res."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1084\/jem.20160712","article-title":"Early Generated B1 B Cells with Restricted BCRs Become Chronic Lymphocytic Leukemia with Continued C-Myc and Low Bmf Expression","volume":"213","author":"Hayakawa","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/0092-8674(92)90123-T","article-title":"Induction of Apoptosis in Fibroblasts by C-Myc Protein","volume":"69","author":"Evan","year":"1992","journal-title":"Cell"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1084\/jem.181.2.699","article-title":"Transfection of the C-Myc Oncogene into Normal Epstein-Barr Virus-Harboring B Cells Results in New Phenotypic and Functional Features Resembling Those of Burkitt Lymphoma Cells and Normal Centroblasts","volume":"181","author":"Cutrona","year":"1995","journal-title":"J. Exp. Med."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1002\/eji.1830270135","article-title":"The Propensity to Apoptosis of Centrocytes and Centroblasts Correlates with Elevated Levels of Intracellular Myc Protein","volume":"27","author":"Cutrona","year":"1997","journal-title":"Eur. J. Immunol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1038\/ni.2418","article-title":"The Cell-Cycle Regulator c-Myc Is Essential for the Formation and Maintenance of Germinal Centers","volume":"13","author":"Calado","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/ni.2428","article-title":"The Proto-Oncogene MYC Is Required for Selection in the Germinal Center and Cyclic Reentry","volume":"13","author":"Victora","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"e722","DOI":"10.1097\/HS9.0000000000000722","article-title":"B-Cell Receptor Signaling Induced Metabolic Alterations in Chronic Lymphocytic Leukemia Can Be Partially Bypassed by TP53 Abnormalities","volume":"6","author":"Kluckova","year":"2022","journal-title":"HemaSphere"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"e265","DOI":"10.3324\/haematol.2014.120824","article-title":"Higher Levels of Reactive Oxygen Species Are Associated with Anergy in Chronic Lymphocytic Leukemia","volume":"100","author":"Linley","year":"2015","journal-title":"Haematologica"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"18078","DOI":"10.1073\/pnas.1411390111","article-title":"Enhanced Activation of an Amino-Terminally Truncated Isoform of the Voltage-Gated Proton Channel HVCN1 Enriched in Malignant B Cells","volume":"111","author":"Hondares","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1182\/blood-2007-09-111344","article-title":"Constitutive Activation of Distinct BCR-Signaling Pathways in a Subset of CLL Patients: A Molecular Signature of Anergy","volume":"112","author":"Muzio","year":"2008","journal-title":"Blood"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"4424","DOI":"10.1182\/blood-2006-11-056648","article-title":"Reversible Anergy of SIgM-Mediated Signaling in the Two Subsets of CLL Defined by VH-Gene Mutational Status","volume":"109","author":"Mockridge","year":"2007","journal-title":"Blood"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"3879","DOI":"10.1182\/blood-2012-12-474718","article-title":"Targeting B-Cell Anergy in Chronic Lymphocytic Leukemia","volume":"121","author":"Apollonio","year":"2013","journal-title":"Blood"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1038\/leu.2011.152","article-title":"Lyn-Mediated SHP-1 Recruitment to CD5 Contributes to Resistance to Apoptosis of B-Cell Chronic Lymphocytic Leukemia Cells","volume":"25","author":"Tibaldi","year":"2011","journal-title":"Leukemia"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/nature03724","article-title":"Cellular and Genetic Mechanisms of Self Tolerance and Autoimmunity","volume":"435","author":"Goodnow","year":"2005","journal-title":"Nature"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/imr.12820","article-title":"Understanding and Measuring Human B-Cell Tolerance and Its Breakdown in Autoimmune Disease","volume":"292","author":"Cashman","year":"2019","journal-title":"Immunol. Rev."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1084\/jem.20080611","article-title":"Functional Anergy in a Subpopulation of Naive B Cells from Healthy Humans That Express Autoreactive Immunoglobulin Receptors","volume":"206","author":"Duty","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"104198","DOI":"10.1016\/j.dci.2021.104198","article-title":"Immunoglobulin D and Its Encoding Genes: An Updated Review","volume":"124","author":"Wan","year":"2021","journal-title":"Dev. Comp. Immunol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/ni.3141","article-title":"Responsiveness of B Cells Is Regulated by the Hinge Region of IgD","volume":"16","author":"Hug","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"e149308","DOI":"10.1172\/JCI149308","article-title":"B Cell Receptor Isotypes Differentially Associate with Cell Signaling, Kinetics, and Outcome in Chronic Lymphocytic Leukemia","volume":"132","author":"Mazzarello","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"ra93","DOI":"10.1126\/scisignal.2005887","article-title":"B Cell Antigen Receptors of the IgM and IgD Classes Are Clustered in Different Protein Islands That Are Altered during B Cell Activation","volume":"8","author":"Maity","year":"2015","journal-title":"Sci. Signal."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"e02069","DOI":"10.7554\/eLife.02069","article-title":"B Cell Activation Involves Nanoscale Receptor Reorganizations and Inside-out Signaling by Syk","volume":"3","author":"Maity","year":"2014","journal-title":"eLife"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.4049\/jimmunol.1600915","article-title":"Functional Differences between IgM and IgD Signaling in Chronic Lymphocytic Leukemia","volume":"197","author":"Sivina","year":"2016","journal-title":"J. Immunol. Baltim."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1007\/s00277-016-2788-6","article-title":"BCR and Chemokine Responses upon Anti-IgM and Anti-IgD Stimulation in Chronic Lymphocytic Leukaemia","volume":"95","author":"Haerzschel","year":"2016","journal-title":"Ann. Hematol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1182\/blood.V95.4.1199.004k21_1199_1206","article-title":"Apoptosis or Plasma Cell Differentiation of CD38-Positive B-Chronic Lymphocytic Leukemia Cells Induced by Cross-Linking of Surface IgM or IgD","volume":"95","author":"Zupo","year":"2000","journal-title":"Blood"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"13381","DOI":"10.1038\/ncomms13381","article-title":"IgD Attenuates the IgM-Induced Anergy Response in Transitional and Mature B Cells","volume":"7","author":"Sabouri","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"4040","DOI":"10.4049\/jimmunol.1100532","article-title":"TOSO, the Fcmicro Receptor, Is Highly Expressed on Chronic Lymphocytic Leukemia B Cells, Internalizes upon IgM Binding, Shuttles to the Lysosome, and Is Downregulated in Response to TLR Activation","volume":"187","author":"Vire","year":"2011","journal-title":"J. Immunol. Baltim."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.1084\/jem.20091107","article-title":"Identity of the Elusive IgM Fc Receptor (FcmuR) in Humans","volume":"206","author":"Kubagawa","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_178","first-page":"834","article-title":"Intraclonal Cell Expansion and Selection Driven by B Cell Receptor in Chronic Lymphocytic Leukemia","volume":"17","author":"Colombo","year":"2011","journal-title":"Mol. Med. Camb. Mass"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1016\/S0140-6736(18)30422-7","article-title":"Chronic Lymphocytic Leukaemia","volume":"391","author":"Hallek","year":"2018","journal-title":"Lancet Lond. Engl."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1182\/blood-2018-11-846808","article-title":"How I Manage Ibrutinib Intolerance and Complications in Patients with Chronic Lymphocytic Leukemia","volume":"133","author":"Stephens","year":"2019","journal-title":"Blood"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1002\/cncr.31931","article-title":"Chronic Lymphocytic Leukemia (CLL) Treatment: So Many Choices, Such Great Options","volume":"125","author":"Sharma","year":"2019","journal-title":"Cancer"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1056\/NEJMoa1215637","article-title":"Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia","volume":"369","author":"Byrd","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1182\/blood-2013-09-527853","article-title":"Prolonged Lymphocytosis during Ibrutinib Therapy Is Associated with Distinct Molecular Characteristics and Does Not Indicate a Suboptimal Response to Therapy","volume":"123","author":"Woyach","year":"2014","journal-title":"Blood"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"1910","DOI":"10.1182\/blood-2017-10-810044","article-title":"Single-Agent Ibrutinib in Treatment-Na\u00efve and Relapsed\/Refractory Chronic Lymphocytic Leukemia: A 5-Year Experience","volume":"131","author":"Furman","year":"2018","journal-title":"Blood"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1200\/JCO.19.03355","article-title":"ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia","volume":"38","author":"Ghia","year":"2020","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1182\/blood.2020009165","article-title":"MARCKS Affects Cell Motility and Response to BTK Inhibitors in CLL","volume":"138","author":"Beckmann","year":"2021","journal-title":"Blood"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1158\/1078-0432.CCR-18-1286","article-title":"Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic Lymphocytic Leukemia Patients","volume":"25","author":"Drennan","year":"2019","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1182\/blood.2021011650","article-title":"CLL Cells Are Moved by the MARCKS Brothers","volume":"138","author":"Burger","year":"2021","journal-title":"Blood"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1182\/blood-2016-04-709519","article-title":"Ibrutinib Inhibits CD20 Upregulation on CLL B Cells Mediated by the CXCR4\/SDF-1 Axis","volume":"128","author":"Pavlasova","year":"2016","journal-title":"Blood"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"11589","DOI":"10.1038\/ncomms11589","article-title":"Clonal Evolution in Patients with Chronic Lymphocytic Leukaemia Developing Resistance to BTK Inhibition","volume":"7","author":"Burger","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1182\/blood-2015-02-626846","article-title":"Hypermorphic Mutation of Phospholipase C, \u03932 Acquired in Ibrutinib-Resistant CLL Confers BTK Independency upon B-Cell Receptor Activation","volume":"126","author":"Liu","year":"2015","journal-title":"Blood"},{"key":"ref_192","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_193","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1182\/blood-2007-04-087882","article-title":"The Opposite Effects of IL-15 and IL-21 on CLL B Cells Correlate with Differential Activation of the JAK\/STAT and ERK1\/2 Pathways","volume":"111","author":"Meazza","year":"2008","journal-title":"Blood"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1182\/asheducation-2011.1.96","article-title":"Nurture versus Nature: The Microenvironment in Chronic Lymphocytic Leukemia","volume":"2011","author":"Burger","year":"2011","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1182\/blood-2015-06-650804","article-title":"Interleukin-6 in CLL: Accelerator or Brake?","volume":"126","author":"Lapalombella","year":"2015","journal-title":"Blood"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/sj.leu.2404456","article-title":"Toll-like Receptor Agonists in the Treatment of Chronic Lymphocytic Leukemia","volume":"21","author":"Spaner","year":"2007","journal-title":"Leukemia"},{"key":"ref_197","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-1alpha","volume":"106","author":"Nishio","year":"2005","journal-title":"Blood"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1078\/0171-2985-00192","article-title":"Bruton\u2019s Tyrosine Kinase Is Activated upon CD40 Stimulation in Human B Lymphocytes","volume":"206","author":"Brunner","year":"2002","journal-title":"Immunobiology"},{"key":"ref_199","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_200","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1016\/j.jaci.2013.12.1085","article-title":"Bruton Tyrosine Kinase Mediates TLR9-Dependent Human Dendritic Cell Activation","volume":"133","author":"Lougaris","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"95","DOI":"10.3389\/fimmu.2019.00095","article-title":"Toll-Like Receptor Signaling Drives Btk-Mediated Autoimmune Disease","volume":"10","author":"Rip","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_202","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. Baltim."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"3064","DOI":"10.1182\/blood.2020005964","article-title":"TLR9 Expression in Chronic Lymphocytic Leukemia Identifies a Promigratory Subpopulation and Novel Therapeutic Target","volume":"137","author":"Kennedy","year":"2021","journal-title":"Blood"},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"5041","DOI":"10.1182\/blood-2009-03-213363","article-title":"Toll-like Receptor 9 Signaling by CpG-B Oligodeoxynucleotides Induces an Apoptotic Pathway in Human Chronic Lymphocytic Leukemia B Cells","volume":"115","author":"Liang","year":"2010","journal-title":"Blood"},{"key":"ref_205","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_206","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_207","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_208","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_209","doi-asserted-by":"crossref","first-page":"eaal1571","DOI":"10.1126\/scitranslmed.aal1571","article-title":"Microenvironmental Regulation of the IL-23R\/IL-23 Axis Overrides Chronic Lymphocytic Leukemia Indolence","volume":"10","author":"Cutrona","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"5593","DOI":"10.1182\/bloodadvances.2021005726","article-title":"MiR-146b-5p Regulates Il-23 Receptor Complex Expression in Chronic Lymphocytic Leukemia Cells","volume":"6","author":"Matis","year":"2022","journal-title":"Blood Adv."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1182\/blood-2018-01-791376","article-title":"Biology and Treatment of Richter Syndrome","volume":"131","author":"Rossi","year":"2018","journal-title":"Blood"},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s11912-020-01001-x","article-title":"Richter Syndrome","volume":"23","author":"Condoluci","year":"2021","journal-title":"Curr. Oncol. Rep."},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1097\/PAS.0b013e31804bdaf8","article-title":"IgVH Mutational Status and Clonality Analysis of Richter\u2019s Transformation: Diffuse Large B-Cell Lymphoma and Hodgkin Lymphoma in Association with B-Cell Chronic Lymphocytic Leukemia (B-CLL) Represent 2 Different Pathways of Disease Evolution","volume":"31","author":"Mao","year":"2007","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.1182\/blood-2010-09-302174","article-title":"The Genetics of Richter Syndrome Reveals Disease Heterogeneity and Predicts Survival after Transformation","volume":"117","author":"Rossi","year":"2011","journal-title":"Blood"},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1182\/blood-2013-03-489518","article-title":"Two Main Genetic Pathways Lead to the Transformation of Chronic Lymphocytic Leukemia to Richter Syndrome","volume":"122","author":"Chigrinova","year":"2013","journal-title":"Blood"},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1084\/jem.20131448","article-title":"Genetic Lesions Associated with Chronic Lymphocytic Leukemia Transformation to Richter Syndrome","volume":"210","author":"Fabbri","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1182\/blood.2020008276","article-title":"B-Cell Receptor Signaling and Genetic Lesions in TP53 and CDKN2A\/CDKN2B Cooperate in Richter Transformation","volume":"138","author":"Chakraborty","year":"2021","journal-title":"Blood"},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"4415","DOI":"10.1158\/1078-0432.CCR-08-3266","article-title":"Stereotyped B-Cell Receptor Is an Independent Risk Factor of Chronic Lymphocytic Leukemia Transformation to Richter Syndrome","volume":"15","author":"Rossi","year":"2009","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1182\/blood-2014-12-610782","article-title":"The Efficacy of Ibrutinib in the Treatment of Richter Syndrome","volume":"125","author":"Tsang","year":"2015","journal-title":"Blood"},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"e277","DOI":"10.1038\/bcj.2014.98","article-title":"Ibrutinib Has Some Activity in Richter\u2019s Syndrome","volume":"5","author":"Giri","year":"2015","journal-title":"Blood Cancer J."},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"e912","DOI":"10.1016\/S2352-3026(21)00305-7","article-title":"Acalabrutinib Monotherapy for Treatment of Chronic Lymphocytic Leukaemia (ACE-CL-001): Analysis of the Richter Transformation Cohort of an Open-Label, Single-Arm, Phase 1-2 Study","volume":"8","author":"Eyre","year":"2021","journal-title":"Lancet Haematol."},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1084\/jem.20011693","article-title":"Chronic Lymphocytic Leukemia B Cells Can Undergo Somatic Hypermutation and Intraclonal Immunoglobulin V(H)DJ(H) Gene Diversification","volume":"196","author":"Gurrieri","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1182\/blood-2006-05-020644","article-title":"Progressive Immunoglobulin Gene Mutations in Chronic Lymphocytic Leukemia: Evidence for Antigen-Driven Intraclonal Diversification","volume":"109","author":"Volkheimer","year":"2007","journal-title":"Blood"},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.1365-2141.2005.05974.x","article-title":"IgV Gene Intraclonal Diversification and Clonal Evolution in B-Cell Chronic Lymphocytic Leukaemia","volume":"133","author":"Bagnara","year":"2006","journal-title":"Br. J. Haematol."},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"4460","DOI":"10.1182\/blood-2009-05-221309","article-title":"Extensive Intraclonal Diversification in a Subgroup of Chronic Lymphocytic Leukemia Patients with Stereotyped IGHV4-34 Receptors: Implications for Ongoing Interactions with Antigen","volume":"114","author":"Sutton","year":"2009","journal-title":"Blood"},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"13081","DOI":"10.1073\/pnas.0801523105","article-title":"Subclonal Phylogenetic Structures in Cancer Revealed by Ultra-Deep Sequencing","volume":"105","author":"Campbell","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"640731","DOI":"10.3389\/fonc.2021.640731","article-title":"Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course","volume":"11","author":"Bagnara","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1146\/annurev-immunol-120419-022408","article-title":"Germinal Centers","volume":"40","author":"Victora","year":"2022","journal-title":"Annu. Rev. Immunol."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"634383","DOI":"10.3389\/fonc.2021.634383","article-title":"AID in Chronic Lymphocytic Leukemia: Induction and Action during Disease Progression","volume":"11","author":"Oppezzo","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1038\/s41375-020-0723-2","article-title":"Clinical Significance of TP53, BIRC3, ATM and MAPK-ERK Genes in Chronic Lymphocytic Leukaemia: Data from the Randomised UK LRF CLL4 Trial","volume":"34","author":"Blakemore","year":"2020","journal-title":"Leukemia"},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"789","DOI":"10.3324\/haematol.2018.195818","article-title":"Deep Targeted Sequencing of TP53 in Chronic Lymphocytic Leukemia: Clinical Impact at Diagnosis and at Time of Treatment","volume":"104","author":"Brieghel","year":"2019","journal-title":"Haematologica"},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"5566","DOI":"10.1158\/1078-0432.CCR-21-0701","article-title":"TP53 Mutations with Low Variant Allele Frequency Predict Short Survival in Chronic Lymphocytic Leukemia","volume":"27","author":"Bomben","year":"2021","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1182\/blood.2020009530","article-title":"Low-Burden TP53 Mutations in CLL: Clinical Impact and Clonal Evolution within the Context of Different Treatment Options","volume":"138","author":"Malcikova","year":"2021","journal-title":"Blood"},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"3693","DOI":"10.1002\/j.1460-2075.1988.tb03251.x","article-title":"Germline Antibody V Regions as Determinants of Clonal Persistence and Malignant Growth in the B Cell Compartment","volume":"7","author":"Gu","year":"1988","journal-title":"EMBO J."},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1002\/eji.1830170414","article-title":"Expansion and Functional Activity of Ly-1+ B Cells upon Transfer of Peritoneal Cells into Allotype-Congenic, Newborn Mice","volume":"17","author":"Rajewsky","year":"1987","journal-title":"Eur. J. Immunol."},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1038\/leu.2016.61","article-title":"Loss of a Chromosomal Region with Synteny to Human 13q14 Occurs in Mouse Chronic Lymphocytic Leukemia That Originates from Early-Generated B-1 B Cells","volume":"30","author":"Hayakawa","year":"2016","journal-title":"Leukemia"},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"11713","DOI":"10.1073\/pnas.0604564103","article-title":"B Cell Receptors in TCL1 Transgenic Mice Resemble Those of Aggressive, Treatment-Resistant Human Chronic Lymphocytic Leukemia","volume":"103","author":"Yan","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1182\/blood-2013-07-515361","article-title":"Bruton\u2019s Tyrosine Kinase (BTK) Function Is Important to the Development and Expansion of Chronic Lymphocytic Leukemia (CLL)","volume":"123","author":"Woyach","year":"2014","journal-title":"Blood"},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.3324\/haematol.2021.279924","article-title":"B-Cell Antigen Receptor Expression and Phosphatidylinositol 3-Kinase Signaling Regulate Genesis and Maintenance of Mouse Chronic Lymphocytic Leukemia","volume":"107","author":"Schmid","year":"2022","journal-title":"Haematologica"},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1084\/jem.194.11.1639","article-title":"Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia","volume":"194","author":"Rosenwald","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1084\/jem.194.11.1625","article-title":"Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells","volume":"194","author":"Klein","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"4141","DOI":"10.1158\/1078-0432.CCR-13-2497","article-title":"MicroRNAome Expression in Chronic Lymphocytic Leukemia: Comparison with Normal B-Cell Subsets and Correlations with Prognostic and Clinical Parameters","volume":"20","author":"Negrini","year":"2014","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1158\/2159-8290.CD-13-0349","article-title":"Evolution of DNA Methylation Is Linked to Genetic Aberrations in Chronic Lymphocytic Leukemia","volume":"4","author":"Oakes","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"eaau6085","DOI":"10.1126\/sciimmunol.aau6085","article-title":"Structure and Function of the Immune System in the Spleen","volume":"4","author":"Lewis","year":"2019","journal-title":"Sci. Immunol."},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"683","DOI":"10.3389\/fimmu.2018.00683","article-title":"Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective","volume":"9","author":"Darwiche","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ccr.2011.08.001","article-title":"Surprise! HSC Are Aberrant in Chronic Lymphocytic Leukemia","volume":"20","author":"Alizadeh","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"751","DOI":"10.3324\/haematol.2018.191098","article-title":"Age-Related Clonal Hematopoiesis and Monoclonal B-Cell Lymphocytosis\/Chronic Lymphocytic Leukemia: A New Association?","volume":"103","author":"Condoluci","year":"2018","journal-title":"Haematologica"},{"key":"ref_248","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_249","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_250","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1056\/NEJMra1406186","article-title":"Myeloproliferative Neoplasms","volume":"376","author":"Spivak","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_251","doi-asserted-by":"crossref","first-page":"eaan4673","DOI":"10.1126\/science.aan4673","article-title":"Clonal Hematopoiesis in Human Aging and Disease","volume":"366","author":"Jaiswal","year":"2019","journal-title":"Science"},{"key":"ref_252","doi-asserted-by":"crossref","first-page":"329","DOI":"10.3324\/haematol.2013.087593","article-title":"Multiple Productive Immunoglobulin Heavy Chain Gene Rearrangements in Chronic Lymphocytic Leukemia Are Mostly Derived from Independent Clones","volume":"99","author":"Plevova","year":"2014","journal-title":"Haematologica"},{"key":"ref_253","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1038\/leu.2015.351","article-title":"Next-Generation IgVH Sequencing CLL-like Monoclonal B-Cell Lymphocytosis Reveals Frequent Oligoclonality and Ongoing Hypermutation","volume":"30","author":"Klinger","year":"2016","journal-title":"Leukemia"},{"key":"ref_254","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/leu.2017.274","article-title":"Multiple Productive IGH Rearrangements Denote Oligoclonality Even in Immunophenotypically Monoclonal CLL","volume":"32","author":"Brazdilova","year":"2018","journal-title":"Leukemia"},{"key":"ref_255","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1038\/ng.2652","article-title":"Genome-Wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia","volume":"45","author":"Berndt","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_256","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/ng.2843","article-title":"A Genome-Wide Association Study Identifies Multiple Susceptibility Loci for Chronic Lymphocytic Leukemia","volume":"46","author":"Speedy","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_257","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1158\/2159-8290.CD-14-0104","article-title":"Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients","volume":"4","author":"Damm","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_258","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1038\/leu.2017.343","article-title":"Somatic CLL Mutations Occur at Multiple Distinct Hematopoietic Maturation Stages: Documentation and Cautionary Note Regarding Cell Fraction Purity","volume":"32","author":"Marsilio","year":"2018","journal-title":"Leukemia"},{"key":"ref_259","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13045-017-0450-y","article-title":"Next-Generation Sequencing and FISH Studies Reveal the Appearance of Gene Mutations and Chromosomal Abnormalities in Hematopoietic Progenitors in Chronic Lymphocytic Leukemia","volume":"10","author":"Robledo","year":"2017","journal-title":"J. Hematol. Oncol."},{"key":"ref_260","doi-asserted-by":"crossref","first-page":"865","DOI":"10.3324\/haematol.2017.177212","article-title":"Highly Similar Genomic Landscapes in Monoclonal B-Cell Lymphocytosis and Ultra-Stable Chronic Lymphocytic Leukemia with Low Frequency of Driver Mutations","volume":"103","author":"Agathangelidis","year":"2018","journal-title":"Haematologica"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14249\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:20:26Z","timestamp":1760145626000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14249"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,17]]},"references-count":260,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232214249"],"URL":"https:\/\/doi.org\/10.3390\/ijms232214249","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,17]]}}}