Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed "satellites," were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.

1st Department of Propaedeutic Medicine University of Athens Athens Greece

2nd Medical Department University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Assistance Publique Hôpitaux de Paris Hôpital Pitié Salpêtrière Department of Biological Hematology Sorbonne Université UMR_S 1138 Centre de Recherche des Cordeliers Paris France

Center of Molecular Medicine Central European Institute of Technology Masaryk University Brno Czech Republic

Centro de Investigacion Biomedica en Red en Oncologia Madrid Spain

Clinic for Hematology Clinical Center of Serbia Belgrade Serbia

Clinical Genetics Karolinska University Laboratory Karolinska University Hospital Stockholm Sweden

Clinical Haematology Belfast City Hospital Belfast Health and Social Care Trust Belfast United Kingdom

Deparment of Hematology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department 1 of Internal Medicine University of Cologne Cologne Germany

Department of Experimental Medicine University of Genoa Genoa Italy

Department of Haematology Royal Bournemouth Hospital Bournemouth United Kingdom

Department of Hematology Amsterdam Infection and Immunity Institute Cancer Center Amsterdam Amsterdam UMC University of Amsterdam Amsterdam The Netherlands

Department of Hematology Faculty of Medicine Ss Cyril and Methodius University of Skopje Skopje Republic of Northern Macedonia

Department of Immunology Mayo Clinic Rochester MN

Department of Immunology Mayo Clinic Scottsdale AZ

Department of Internal Medicine 3 Ulm University Ulm Germany

Department of Internal Medicine Hematology and Oncology Faculty of Medicine Masaryk University University Hospital Brno Brno Czech Republic

Department of Laboratory Medicine Medical University of Vienna Vienna Austria

Department of Medicine Faculty of Medicine Kuwait University Safat Kuwait

Department of Molecular Biology and Genetics Democritus University of Thrace Alexandroupolis Greece

Department of Molecular Medicine and Surgery Karolinska Institute Stockholm Sweden

Division of Hematology Department of Translational Medicine University of Eastern Piedmont Ospedale Maggiore della Carità Novara Italy

Division of Hematology Oncology Institute of Southern Switzerland Bellinzona Switzerland

Division of Immunology Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute Milan Italy

Experimental Hematooncology Department Medical University of Lublin Lublin Poland

Faculty of Pharmacy Ss Cyril and Methodius University of Skopje Skopje Republic of Northern Macedonia

General Anatomopathology and Molecular Oncogenetics Azienda Ospedaliero Universitaria City of Health and Science of Turin Turin Italy

Hammersmith Hospital London United Kingdom

Hematocrit Unit Hematology Department G Papanicolaou Hospital Thessaloniki Greece

Hematology and Clinical Immunology Unit Department of Medicine University of Padua Padua Italy

Hematology Department Nikea General Hospital Pireaus Greece; and

Hospital Clinic of Barcelona University of Barcelona Barcelona Spain

Institut d'Investigacions Biomediques August Pi 1 Sunyer Barcelona Spain

Institute of Applied Biosciences Centre for Research and Technology Hellas Thessaloniki Greece

Institute of Molecular Genetics and Genetic Engineering University of Belgrade Belgrade Serbia

International ImMunoGeneTics Information System Université de Montpellier Montpellier France

Karaiskakio Foundation Nicosia Cyprus

Laboratorio de Citogenètica Molecular Laboratori de Citologia Hematològica Servei de Patologia i Servei de Hematologia Hospital del Mar Barcelona Spain

Laboratory Medical Immunology Department of Immunology Erasmus MC University Medical Center Rotterdam The Netherlands

MLL Munich Leukemia Laboratory Munich Germany

Molecular Pathology Unit Haematology Department Niguarda Cancer Center Niguarda Hospital Milan Italy

MTA SE Momentum Molecular Oncohematology Research Group 1st Department of Pathology and Experimental Cancer Research Semmelweis University Budapest Hungary

National Research Center for Hematology Moscow Russia

Science for Life Laboratory Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Strategic Research Program on CLL B Cell Neoplasia Unit Division of Experimental Oncology Università Vita Salute San Raffaele Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele Milan Italy

The Center for the Study of Haematological Malignancies Nicosia Cyprus

The Feinstein Institute for Medical Research Northwell Health Manhasset NY

University Hospital Cologne Cologne Germany

University Hospital Medical Center Ulm Germany

UO Molecular Pathology IRCCS Ospedale Policlinico San Martino Genoa Italy

Veneto Institute of Molecular Medicine Padua Italy

Zobrazit více v PubMed

Sutton LA, Rosenquist R. The complex interplay between cell-intrinsic and cell-extrinsic factors driving the evolution of chronic lymphocytic leukemia. Semin Cancer Biol. 2015;34:22-35. PubMed

Puente XS, Jares P, Campo E. Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions. Blood. 2018;131(21):2283-2296. PubMed

Byrd JC, Furman RR, Coutre SE, et al. . Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506. PubMed PMC

Jones JA, Robak T, Brown JR, et al. . Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017;4(3):e114-e126. PubMed

Brown JR, Hillmen P, O’Brien S, et al. . Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018;32(1):83-91. PubMed PMC

Fais F, Ghiotto F, Hashimoto S, et al. . Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest. 1998;102(8):1515-1525. PubMed PMC

Damle RN, Wasil T, Fais F, et al. . Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94(6):1840-1847. PubMed

Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848-1854. PubMed

Stevenson FK, Forconi F, Packham G. The meaning and relevance of B-cell receptor structure and function in chronic lymphocytic leukemia. Semin Hematol. 2014;51(3):158-167. PubMed

Langerak AW, Davi F, Stamatopoulos K. Immunoglobulin heavy variable somatic hyper mutation status in chronic lymphocytic leukaemia: on the threshold of a new era? Br J Haematol. 2020;189(5):809-810. PubMed PMC

Stamatopoulos K, Belessi C, Moreno C, et al. . Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: Pathogenetic implications and clinical correlations. Blood. 2007;109(1):259-270. PubMed

Murray F, Darzentas N, Hadzidimitriou A, et al. . Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. Blood. 2008;111(3):1524-1533. PubMed

Bomben R, Dal Bo M, Capello D, et al. . Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: results from an Italian multicentre study. Br J Haematol. 2009;144(4):492-506. PubMed

Darzentas N, Hadzidimitriou A, Murray F, et al. . A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence. Leukemia. 2010;24(1):125-132. PubMed

Agathangelidis A, Darzentas N, Hadzidimitriou A, et al. . Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood. 2012;119(19):4467-4475. PubMed PMC

Catera R, Liu Y, Gao C, et al. . Binding of CLL subset 4 B-cell receptor immunoglobulins to viable human memory B lymphocytes requires a distinctive IGKV somatic mutation. Mol Med. 2017;23(1):1-12. PubMed PMC

Chu CC, Catera R, Hatzi K, et al. . Chronic lymphocytic leukemia antibodies with a common stereotypic rearrangement recognize nonmuscle myosin heavy chain IIA. Blood. 2008;112(13):5122-5129. PubMed PMC

Chu CC, Catera R, Zhang L, et al. . Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin. Blood. 2010;115(19):3907-3915. PubMed PMC

Gounari M, Ntoufa S, Apollonio B, et al. . Excessive antigen reactivity may underlie the clinical aggressiveness of chronic lymphocytic leukemia stereotyped subset #8. Blood. 2015;125(23):3580-3587. PubMed PMC

Seiler T, Woelfle M, Yancopoulos S, et al. . Characterization of structurally defined epitopes recognized by monoclonal antibodies produced by chronic lymphocytic leukemia B cells. Blood. 2009;114(17):3615-3624. PubMed PMC

Malcikova J, Stalika E, Davis Z, et al. . The frequency of TP53 gene defects differs between chronic lymphocytic leukaemia subgroups harbouring distinct antigen receptors. Br J Haematol. 2014;166(4):621-625. PubMed

Navrkalova V, Young E, Baliakas P, et al. . ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres. Haematologica. 2016;101(9):e369-e373. PubMed PMC

Strefford JC, Sutton LA, Baliakas P, et al. . Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2. Leukemia. 2013;27(11):2196-2199. PubMed

Kanduri M, Marincevic M, Halldórsdóttir AM, et al. . Distinct transcriptional control in major immunogenetic subsets of chronic lymphocytic leukemia exhibiting subset-biased global DNA methylation profiles. Epigenetics. 2012;7(12):1435-1442. PubMed PMC

Marincevic M, Mansouri M, Kanduri M, et al. . Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors. Haematologica. 2010;95(12):2072-2079. PubMed PMC

Papakonstantinou N, Ntoufa S, Chartomatsidou E, et al. . Differential microRNA profiles and their functional implications in different immunogenetic subsets of chronic lymphocytic leukemia. Mol Med. 2013;19(1):115-123. PubMed PMC

Papakonstantinou N, Ntoufa S, Tsagiopoulou M, et al. . Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia. Int J Cancer. 2019;144(11):2695-2706. PubMed

Maura F, Cutrona G, Mosca L, et al. . Association between gene and miRNA expression profiles and stereotyped subset #4 B-cell receptor in chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56(11):3150-3158. PubMed

Arvaniti E, Ntoufa S, Papakonstantinou N, et al. . Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients. Haematologica. 2011;96(11):1644-1652. PubMed PMC

Ntoufa S, Vardi A, Papakonstantinou N, et al. . Distinct innate immunity pathways to activation and tolerance in subgroups of chronic lymphocytic leukemia with distinct immunoglobulin receptors. Mol Med. 2012;18(9):1281-1291. PubMed PMC

Ntoufa S, Papakonstantinou N, Apollonio B, et al. . B cell anergy modulated by TLR1/2 and the miR-17∼92 cluster underlies the indolent clinical course of chronic lymphocytic leukemia stereotyped subset #4. J Immunol. 2016;196(10):4410-4417. PubMed

Dühren-von Minden M, Übelhart R, Schneider D, et al. . Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature. 2012;489(7415):309-312. PubMed

Minici C, Gounari M, Übelhart R, et al. . Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia. Nat Commun. 2017;8(1):15746. PubMed PMC

Baliakas P, Agathangelidis A, Hadzidimitriou A, et al. . Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations. Blood. 2015;125(5):856-859. PubMed PMC

Jaramillo S, Agathangelidis A, Schneider C, et al. . Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL Study Group (GCLLSG) [published online ahead of print 20 December 2019]. Haematologica. doi:10.3324/haematol.2019.231027. PubMed PMC

Rossi D, Spina V, Cerri M, et al. . Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res. 2009;15(13):4415-4422. PubMed

Visco C, Maura F, Tuana G, et al. . Immune thrombocytopenia in patients with chronic lymphocytic leukemia is associated with stereotyped B-cell receptors. Clin Cancer Res. 2012;18(7):1870-1878. PubMed

Baliakas P, Hadzidimitriou A, Sutton LA, et al. . Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study. Lancet Haematol. 2014;1(2):e74-e84. PubMed

Del Giudice I, Chiaretti S, Santangelo S, et al. . Stereotyped subset #1 chronic lymphocytic leukemia: a direct link between B-cell receptor structure, function, and patients’ prognosis. Am J Hematol. 2014;89(1):74-82. PubMed

Xochelli A, Baliakas P, Kavakiotis I, et al. . Chronic lymphocytic leukemia with mutated IGHV4-34 receptors: shared and distinct immunogenetic features and clinical outcomes. Clin Cancer Res. 2017;23(17):5292-5301. PubMed

Baliakas P, Mattsson M, Hadzidimitriou A, et al. . No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy. Haematologica. 2018;103(4):e158-e161. PubMed PMC

Baliakas P, Moysiadis T, Hadzidimitriou A, et al. ; European Research Initiative on CLL (ERIC) . Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia. Haematologica. 2019;104(2):360-369. PubMed PMC

Hallek M, Cheson BD, Catovsky D, et al. . iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. PubMed

Rosenquist R, Ghia P, Hadzidimitriou A, et al. . Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations. Leukemia. 2017;31(7):1477-1481. PubMed PMC

Alamyar E, Duroux P, Lefranc MP, Giudicelli V. IMGT(®) tools for the nucleotide analysis of immunoglobulin (IG) and T cell receptor (TR) V-(D)-J repertoires, polymorphisms, and IG mutations: IMGT/V-QUEST and IMGT/HighV-QUEST for NGS. Methods Mol Biol. 2012;882:569-604. PubMed

Agathangelidis A, Psomopoulos F, Stamatopoulos K. Stereotyped B cell receptor immunoglobulins in B cell lymphomas. Methods Mol Biol. 2019;1956:139-155. PubMed

Ten Hacken E, Gounari M, Ghia P, Burger JA. The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia. Leukemia. 2019;33(2):287-298. PubMed PMC

Maura F, Cutrona G, Fabris S, et al. . Relevance of stereotyped B-cell receptors in the context of the molecular, cytogenetic and clinical features of chronic lymphocytic leukemia. PLoS One. 2011;6(8):e24313. PubMed PMC

Moysiadis T, Baliakas P, Rossi D, et al. . Different time-dependent changes of risk for evolution in chronic lymphocytic leukemia with mutated or unmutated antigen B cell receptors. Leukemia. 2019;33(7):1801-1805. PubMed

Belhouachi N, Xochelli A, Boudjoghra M, et al. . Primary vitreoretinal lymphomas display a remarkably restricted immunoglobulin gene repertoire. Blood Adv. 2020;4(7):1357-1366. PubMed PMC

Bikos V, Darzentas N, Hadzidimitriou A, et al. . Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications. Leukemia. 2012;26(7):1638-1646. PubMed

Hadzidimitriou A, Agathangelidis A, Darzentas N, et al. . Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood. 2011;118(11):3088-3095. PubMed

Henry Dunand CJ, Wilson PC. Restricted, canonical, stereotyped and convergent immunoglobulin responses. Philos Trans R Soc Lond B Biol Sci. 2015;370(1676):370. PubMed PMC

Joyce MG, Wheatley AK, Thomas PV, et al. ; NISC Comparative Sequencing Program . Vaccine-induced antibodies that neutralize group 1 and group 2 influenza A viruses. Cell. 2016;166(3):609-623. PubMed PMC

Snir O, Chen X, Gidoni M, et al. . Stereotyped antibody responses target posttranslationally modified gluten in celiac disease. JCI Insight. 2017;2(17):93961. PubMed PMC

Giltiay NV, Giordano D, Clark EA. The plasticity of newly formed B cells. J Immunol. 2019;203(12):3095-3104. PubMed PMC

Vergani S, Bagnara D, Mazzarello AN, et al. . CLL stereotyped IGHV-D-J rearrangements can be detected throughout normal B-cell developmental stages in aged people when using ultra-deep, next generation sequencing techniques [abstract]. Blood. 2016;128(22). Abstract 2028.

Colombo M, Bagnara D, Reverberi D, et al. . Tracing CLL-biased stereotyped immunoglobulin gene rearrangements in normal B cell subsets using a high-throughput immunogenetic approach. Mol Med. 2020;26(1):25. PubMed PMC

Agathangelidis A, Galigalidou C, Scarfò L, et al. . Infrequent “chronic lymphocytic leukemia-specific” immunoglobulin stereotypes in aged individuals with or without low count monoclonal B cell lymphocytosis [published online ahead of print 25 June 2020] [letter]. Haematologica. doi:10.3324/haematol.2020.247908. PubMed PMC

Stamatopoulos K, Agathangelidis A, Rosenquist R, Ghia P. Antigen receptor stereotypy in chronic lymphocytic leukemia. Leukemia. 2017;31(2):282-291. PubMed

Scheid JF, Mouquet H, Ueberheide B, et al. . Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science. 2011;333(6049):1633-1637. PubMed PMC

Wu X, Zhou T, Zhu J, et al. ; NISC Comparative Sequencing Program . Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science. 2011;333(6049):1593-1602. PubMed PMC

Zhou T, Zhu J, Wu X, et al. ; NISC Comparative Sequencing Program . Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies. Immunity. 2013;39(2):245-258. PubMed PMC

Schmidt AG, Therkelsen MD, Stewart S, et al. . Viral receptor-binding site antibodies with diverse germline origins. Cell. 2015;161(5):1026-1034. PubMed PMC

Ekiert DC, Bhabha G, Elsliger MA, et al. . Antibody recognition of a highly conserved influenza virus epitope. Science. 2009;324(5924):246-251. PubMed PMC

Cao Y, Su B, Guo X, et al. . Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells. Cell. 2020;182(1):73-84.e16. PubMed PMC

Polychronidou E, Kalamaras I, Agathangelidis A, et al. . Automated shape-based clustering of 3D immunoglobulin protein structures in chronic lymphocytic leukemia. BMC Bioinformatics. 2018;19(suppl 14):414. PubMed PMC

Forconi F, Potter KN, Sozzi E, et al. . The IGHV1-69/IGHJ3 recombinations of unmutated CLL are distinct from those of normal B cells. Blood. 2012;119(9):2106-2109. PubMed

Forconi F, Potter KN, Wheatley I, et al. . The normal IGHV1-69-derived B-cell repertoire contains stereotypic patterns characteristic of unmutated CLL. Blood. 2010;115(1):71-77. PubMed

Hervé M, Xu K, Ng YS, et al. . Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J Clin Invest. 2005;115(6):1636-1643. PubMed PMC

Borche L, Lim A, Binet JL, Dighiero G. Evidence that chronic lymphocytic leukemia B lymphocytes are frequently committed to production of natural autoantibodies. Blood. 1990;76(3):562-569. PubMed

Baliakas P, Hadzidimitriou A, Sutton L-A, et al. . Differential distribution of recurrent gene mutations in subsets of chronic lymphocytic leukemia patients with stereotyped B-cell receptors: results from a multicenter project of the European Research Initiative on CLL in a series of 2482 cases [abstract]. Blood. 2013;122(21). Abstract 4113.

Sutton LA, Young E, Baliakas P, et al. ; ERIC, the European Research Initiative on CLL . Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors. Haematologica. 2016;101(8):959-967. PubMed PMC

Xu JL, Davis MM. Diversity in the CDR3 region of V(H) is sufficient for most antibody specificities. Immunity. 2000;13(1):37-45. PubMed

Hadzidimitriou A, Darzentas N, Murray F, et al. . Evidence for the significant role of immunoglobulin light chains in antigen recognition and selection in chronic lymphocytic leukemia. Blood. 2009;113(2):403-411. PubMed

Kostareli E, Sutton LA, Hadzidimitriou A, et al. . Intraclonal diversification of immunoglobulin light chains in a subset of chronic lymphocytic leukemia alludes to antigen-driven clonal evolution. Leukemia. 2010;24(7):1317-1324. PubMed

Stamatopoulos K, Belessi C, Hadzidimitriou A, et al. . Immunoglobulin light chain repertoire in chronic lymphocytic leukemia. Blood. 2005;106(10):3575-3583. PubMed

Stamatopoulos B, Smith T, Crompot E, et al. . The light chain IgLV3-21 defines a new poor prognostic subgroup in chronic lymphocytic leukemia: results of a multicenter study. Clin Cancer Res. 2018;24(20):5048-5057. PubMed

Maity PC, Bilal M, Koning MT, et al. . IGLV3-21*01 is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling. Proc Natl Acad Sci USA. 2020;117(8):4320-4327. PubMed PMC

Wiehe K, Easterhoff D, Luo K, et al. . Antibody light-chain-restricted recognition of the site of immune pressure in the RV144 HIV-1 vaccine trial is phylogenetically conserved. Immunity. 2014;41(6):909-918. PubMed PMC

Realizing precision medicine in chronic lymphocytic leukemia: Remaining challenges and potential opportunities

The EHA Research Roadmap: Malignant Lymphoid Diseases

Consistent B Cell Receptor Immunoglobulin Features Between Siblings in Familial Chronic Lymphocytic Leukemia