{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:02:16Z","timestamp":1790766136617,"version":"4.1.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Chronic lymphocytic leukemia (CLL) is characterized by a highly biased B-cell receptor (BcR) immunoglobulin repertoire and by recurrent stereotyped receptors defined as quasi-identical BcR recurring in unrelated patients. High-throughput sequencing studies have shown that immunoglobulin rearrangements resembling these CLL stereotypes can also be detected in healthy individuals. Beyond their relevance to leukemogenesis, these findings provide a distinctive opportunity to investigate how recurrent BcR configurations are generated, selected, and maintained during normal B-cell development. In this review, we examine the occurrence of CLL-like stereotyped immunoglobulin rearrangements in healthy repertoires and discuss their implications for normal B-cell biology. Available studies indicate that these rearrangements are physiological components of the repertoire, detectable in cord blood, bone marrow, spleen, and peripheral blood, and distributed across transitional, na\u00efve, marginal zone-like, and memory B-cell compartments. Their representation is non-random and subset specific, suggesting that different receptor configurations are subject to distinct developmental, tolerance, and antigen-driven selection pressures. Some rearrangements are preferentially associated with antigen-inexperienced compartments, whereas others are more frequently found in post-germinal-center populations, partially recapitulating the mutational context of their leukemic counterparts. However, healthy B cells generally lack the stringent light-chain restriction observed in established CLL subsets, indicating that leukemic stereotypy results from additional receptor refinement and clonal selection. Overall, the study of CLL-like stereotypes in healthy individuals extends beyond the identification of putative leukemic precursors. It reveals how convergent receptor architectures arise within physiological immunity, how autoreactive or polyreactive configurations may escape complete censoring, and how normal B-cell repertoires accommodate recurrent immunogenetic solutions without necessarily progressing to malignancy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1949983","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:18:52Z","timestamp":1790763532000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Stereotyped CLL-like immunoglobulin rearrangements in healthy repertoires: implications for leukemogenesis"],"prefix":"10.3389","volume":"17","author":[{"given":"Davide","family":"Bagnara","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Colombo","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, AOM - IRCCS Ospedale Policlinico San Martino","place":["Genova, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Ghiotto","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niccol\u00f2","family":"Cardente","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Oslo","place":["Oslo, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Cutrona","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, AOM - IRCCS Ospedale Policlinico San Martino","place":["Genova, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manlio","family":"Ferrarini","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Fais","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa","place":["Genoa, Italy"]},{"name":"Molecular Pathology Unit, AOM - IRCCS Ospedale Policlinico San Martino","place":["Genova, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","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 Invest"},{"key":"B2","doi-asserted-by":"publisher","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":"B3","doi-asserted-by":"publisher","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":"B4","doi-asserted-by":"publisher","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":"B5","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v108.11.26.26","article-title":"Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations","volume":"108","author":"Stamatopoulos","year":"2006","journal-title":"Blood"},{"key":"B6","doi-asserted-by":"publisher","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":"B7","doi-asserted-by":"publisher","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":"B8","doi-asserted-by":"publisher","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":"B9","doi-asserted-by":"publisher","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":"B10","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2010.033241","article-title":"Biological and clinical significance of stereotyped B-cell receptors in chronic lymphocytic leukemia","volume":"95","author":"Rossi","year":"2010","journal-title":"Haematologica"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/s2352-3026(14)00005-2","article-title":"Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study","volume":"1","author":"Baliakas","year":"2014","journal-title":"Lancet Haematology"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2016.141812","article-title":"Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors","volume":"101","author":"Sutton","year":"2016","journal-title":"Haematologica"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41375-018-0303-x","article-title":"The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia","volume":"18","author":"Hacken","year":"2018","journal-title":"Leukemia"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.771454","article-title":"Distinctive signaling profiles with distinct biological and clinical implications in aggressive CLL subsets with stereotyped B-cell receptor immunoglobulin","volume":"11","author":"Gerousi","year":"2021","journal-title":"Front Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023012221","article-title":"BTK inhibitors in CLL: second-generation drugs and beyond","volume":"8","author":"Tam","year":"2024","journal-title":"Blood Adv"},{"key":"B16","doi-asserted-by":"publisher","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":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-06-225813","article-title":"The normal IGHV1-69\u2013derived B-cell repertoire contains stereotypic patterns characteristic of unmutated CLL","volume":"115","author":"Forconi","year":"2010","journal-title":"Blood"},{"key":"B18","doi-asserted-by":"publisher","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":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1686107","article-title":"The past, present, and future of anti-idiotype antibodies","volume":"16","author":"Murphy","year":"2025","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0879-y","article-title":"Commonality despite exceptional diversity in the baseline human antibody repertoire","volume":"566","author":"Briney","year":"2019","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41586-019-0934-8","article-title":"High frequency of shared clonotypes in human B cell receptor repertoires","volume":"23","author":"Soto","year":"2019","journal-title":"Nature"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-269-8_8","article-title":"Stereotyped B cell receptors in B cell leukemias and lymphomas","volume":"971","author":"Darzentas","year":"2013","journal-title":"Methods Mol Biol (Clifton NJ)"},{"key":"B23","doi-asserted-by":"publisher","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 Invest"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-11-3485","article-title":"Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted V\u03bb2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope","volume":"101","author":"Tobin","year":"2003","journal-title":"Blood"},{"key":"B25","doi-asserted-by":"publisher","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":"B26","doi-asserted-by":"publisher","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":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.70204","article-title":"CLL\u2010like stereotyped BCRs are equally produced in young and old healthy adults, share features of public clonotypes and may be stuck at a pre\u2010germinal centre stage","volume":"208","author":"Dupont","year":"2026","journal-title":"Br J Haematol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12979-019-0163-x","article-title":"The presence of CLL-associated stereotypic B cell receptors in the normal BCR repertoire from healthy individuals increases with age","volume":"16","author":"Muggen","year":"2019","journal-title":"Immun Ageing"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1112879","article-title":"CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: apparent lack of central and early peripheral tolerance censoring","volume":"13","author":"Vergani","year":"2023","journal-title":"Front Oncol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s10020-020-00151-9","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"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.247908","article-title":"Infrequent \u201cchronic lymphocytic leukemia-specific\u201d immunoglobulin stereotypes in aged individuals with or without low-count monoclonal B-cell lymphocytosis","volume":"106","author":"Agathangelidis","year":"2021","journal-title":"Haematologica"},{"key":"B32","doi-asserted-by":"publisher","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":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz035","article-title":"OLGA: fast computation of generation probabilities of B- and T-cell receptor amino acid sequences and motifs","volume":"35","author":"Sethna","year":"2019","journal-title":"Bioinformatics"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-06-162024","article-title":"Chronic lymphocytic leukemia antibodies with a common stereotypic rearrangement recognize nonmuscle myosin heavy chain IIA","volume":"112","author":"Chu","year":"2008","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1607189","article-title":"Conventional and non-conventional antigen-binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset #4 clones","volume":"16","author":"Liu","year":"2025","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1038\/s41467-025-68040-5","article-title":"Defective cell-autonomous signalling and antigenic polyreactivity of B-cell receptors from chronic lymphocytic leukaemia stereotyped subset 1","volume":"17","author":"Cocomazzi","year":"2025","journal-title":"Nat Commun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature11309","article-title":"Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling","volume":"489","author":"Minden","year":"2012","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.clim.2016.08.020","article-title":"Chronic lymphocytic leukemia immunoglobulins display bacterial reactivity that converges and diverges from auto-\/poly-reactivity and IGHV mutation status","volume":"172","author":"Hatzi","year":"2016","journal-title":"Clin Immunol"},{"key":"B39","doi-asserted-by":"publisher","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":"B40","doi-asserted-by":"publisher","first-page":"1","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":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/antib15020025","article-title":"Immunogenetic architecture of chronic lymphocytic leukemia at early stage: insights from the O-CLL1 cohort","volume":"15","author":"Bagnara","year":"2026","journal-title":"Antibodies"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2025032357","article-title":"The singularity of IGHV4-34 links infection, autoimmunity, and B-cell tumors","volume":"147","author":"Stevenson","year":"2026","journal-title":"Blood"},{"key":"B43","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1111\/imr.12808","article-title":"Clonal redemption and clonal anergy as mechanisms to balance B cell tolerance and immunity","volume":"292","author":"Burnett","year":"2019","journal-title":"Immunol Rev"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502297","article-title":"B cell anergy modulated by TLR1\/2 and the miR-17\u223c92 cluster underlies the indolent clinical course of chronic lymphocytic leukemia stereotyped subset #4","volume":"196","author":"Ntoufa","year":"2016","journal-title":"J Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.7.3777","article-title":"Evidence for involvement of a hydrophobic patch in framework region 1 of human V4-34-encoded Igs in recognition of the red blood cell I antigen","volume":"169","author":"Potter","year":"2002","journal-title":"J Immunol"},{"key":"B46","doi-asserted-by":"publisher","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":"B47","doi-asserted-by":"publisher","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":"Herv\u00e9","year":"2005","journal-title":"J Clin Invest"},{"key":"B48","doi-asserted-by":"publisher","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":"B49","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2013.098384","article-title":"The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy","volume":"99","author":"Packham","year":"2014","journal-title":"Haematologica"},{"key":"B50","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/s41541-025-01133-w","article-title":"Human na\u00efve B cells show evidence of anergy and clonal redemption following vaccination","volume":"10","author":"Dizon","year":"2025","journal-title":"NPJ Vaccines"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-09-600874","article-title":"Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations","volume":"125","author":"Baliakas","year":"2015","journal-title":"Blood"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-025-02797-y","article-title":"Molecular and functional characterization of the B-cell receptor in chronic lymphocytic leukemia-like monoclonal B-cell lymphocytosis","volume":"40","author":"Agathangelidis","year":"2026","journal-title":"Leukemia"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.307","article-title":"Targeted deep sequencing reveals clinically relevant subclonal IgHV rearrangements in chronic lymphocytic leukemia","volume":"31","author":"Stamatopoulos","year":"2017","journal-title":"Leukemia"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2024.286380","article-title":"Chronic lymphocytic leukemia often arises by a multiclonal selection process","volume":"110","author":"Bagnara","year":"2025","journal-title":"Haematologica"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111115","article-title":"Leukemia-initiating HSCs in chronic lymphocytic leukemia reveal clonal leukemogenesis and differential drug sensitivity","volume":"40","author":"Chiang","year":"2022","journal-title":"Cell Rep"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2025029905","article-title":"The landscape and evolution of clonal hematopoiesis in chronic lymphocytic leukemia\u2217","volume":"147","author":"Al-Sawaf","year":"2026","journal-title":"Blood"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.70633","article-title":"Clonal haematopoiesis in chronic lymphocytic leukaemia: Biology, inflammaging and clinical implications in the era of targeted therapy","volume":"16","author":"Martino","year":"2026","journal-title":"Clin Transl Med"},{"key":"B58","doi-asserted-by":"publisher","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":"B59","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-09-603217","article-title":"Excessive antigen reactivity may underlie the clinical aggressiveness of chronic lymphocytic leukemia stereotyped subset #8","volume":"125","author":"Gounari","year":"2015","journal-title":"Blood"},{"key":"B60","doi-asserted-by":"publisher","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":"B61","doi-asserted-by":"publisher","DOI":"10.2119\/2008-00102.catera","article-title":"Chronic lymphocytic leukemia cells recognize conserved epitopes associated with apoptosis and oxidation","volume":"14","author":"Catera","year":"2008","journal-title":"Mol Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1949983\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:18:53Z","timestamp":1790763533000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1949983\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":61,"alternative-id":["10.3389\/fimmu.2026.1949983"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1949983","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]},"article-number":"1949983"}}