{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:35:20Z","timestamp":1790804120146,"version":"4.1.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2013,6,1]],"date-time":"2013-06-01T00:00:00Z","timestamp":1370044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated.<\/jats:p>","DOI":"10.4049\/jimmunol.1300321","type":"journal-article","created":{"date-parts":[[2013,5,2]],"date-time":"2013-05-02T07:57:10Z","timestamp":1367481430000},"page":"5771-5778","source":"Crossref","is-referenced-by-count":22,"title":["Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability"],"prefix":"10.1093","volume":"190","author":[{"given":"Paolo","family":"Marcatili","sequence":"first","affiliation":[{"name":"Department of Physics, Sapienza University of Rome , 00185 Rome,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Ghiotto","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa , 16132 Genoa,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudya","family":"Tenca","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa , 16132 Genoa,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Chailyan","sequence":"additional","affiliation":[{"name":"Department of Physics, Sapienza University of Rome , 00185 Rome,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea N","family":"Mazzarello","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa , 16132 Genoa,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Jie","family":"Yan","sequence":"additional","affiliation":[{"name":"The Feinstein Institute for Medical Research, North Shore\u2013Long Island Jewish Health System , Manhasset, NY 11030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Colombo","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology C, National Institute for Cancer Research , 16132 Genoa,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Albesiano","sequence":"additional","affiliation":[{"name":"The Feinstein Institute for Medical Research, North Shore\u2013Long Island Jewish Health System , Manhasset, NY 11030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Bagnara","sequence":"additional","affiliation":[{"name":"The Feinstein Institute for Medical Research, North Shore\u2013Long Island Jewish Health System , Manhasset, NY 11030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Cutrona","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology C, National Institute for Cancer Research , 16132 Genoa,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fortunato","family":"Morabito","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa di Ematologia, Dipartimento di Medicina Interna, Azienda Ospedaliera di Cosenza , 87100 Cosenza,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa , 16132 Genoa,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manlio","family":"Ferrarini","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology C, National Institute for Cancer Research , 16132 Genoa,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Chiorazzi","sequence":"additional","affiliation":[{"name":"The Feinstein Institute for Medical Research, North Shore\u2013Long Island Jewish Health System , Manhasset, NY 11030"},{"name":"Department of Medicine, North Shore\u2013Long Island Jewish Health System , Manhasset, NY 11030"},{"name":"Department of Medicine, Hofstra North Shore\u2013Long Island Jewish School of Medicine , Hempstead NY 11549"},{"name":"Department of Molecular Medicine, Hofstra North Shore\u2013Long Island Jewish School of Medicine , Hempstead NY 11549"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Tramontano","sequence":"additional","affiliation":[{"name":"Department of Physics, Sapienza University of Rome , 00185 Rome,","place":["Italy"]},{"name":"Istituto Pasteur\u2013Fondazione Cenci Bolognetti , 00185 Rome,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Fais","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa , 16132 Genoa,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,6,1]]},"reference":[{"key":"2025032407032926800_r1","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":"2025032407032926800_r2","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. Invest."},{"key":"2025032407032926800_r3","doi-asserted-by":"crossref","first-page":"300","DOI":"10.2119\/2006-00080.Ghiotto","article-title":"Similarities and differences between the light and heavy chain Ig variable region gene repertoires in chronic lymphocytic leukemia","volume":"12","author":"Ghiotto","year":"2006","journal-title":"Mol. Med."},{"key":"2025032407032926800_r4","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1182\/blood-2008-07-166868","article-title":"Evidence for the significant role of immunoglobulin light chains in antigen recognition and selection in chronic lymphocytic leukemia","volume":"113","author":"Hadzidimitriou","year":"2009","journal-title":"Blood"},{"key":"2025032407032926800_r5","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":"2025032407032926800_r6","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":"2025032407032926800_r7","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. Invest."},{"key":"2025032407032926800_r8","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":"2025032407032926800_r9","doi-asserted-by":"crossref","first-page":"4952","DOI":"10.1182\/blood-2002-11-3485","article-title":"Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted Vlambda2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope","volume":"101","author":"Tobin","year":"2003","journal-title":"Blood"},{"key":"2025032407032926800_r10","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":"2025032407032926800_r11","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":"2025032407032926800_r12","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":"2025032407032926800_r13","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1182\/blood-2007-07-099564","article-title":"Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis","volume":"111","author":"Murray","year":"2008","journal-title":"Blood"},{"key":"2025032407032926800_r14","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":"2025032407032926800_r15","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":"Minden","year":"2012","journal-title":"Nature."},{"key":"2025032407032926800_r16","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":"2025032407032926800_r17","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":"Thors\u00e9lius","year":"2006","journal-title":"Blood"},{"key":"2025032407032926800_r18","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1084\/jem.132.2.211","article-title":"An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity","volume":"132","author":"Wu","year":"1970","journal-title":"J. Exp. Med."},{"key":"2025032407032926800_r19","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/0022-2836(87)90412-8","article-title":"Canonical structures for the hypervariable regions of immunoglobulins","volume":"196","author":"Chothia","year":"1987","journal-title":"J. Mol. Biol."},{"key":"2025032407032926800_r20","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1006\/jmbi.1997.1442","article-title":"Conformations of the third hypervariable region in the VH domain of immunoglobulins","volume":"275","author":"Morea","year":"1998","journal-title":"J. Mol. Biol."},{"key":"2025032407032926800_r21","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S0022-2836(05)80102-0","article-title":"Framework residue 71 is a major determinant of the position and conformation of the second hypervariable region in the VH domains of immunoglobulins","volume":"215","author":"Tramontano","year":"1990","journal-title":"J. Mol. Biol."},{"key":"2025032407032926800_r22","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1093\/bioinformatics\/btn341","article-title":"PIGS: automatic prediction of antibody structures","volume":"24","author":"Marcatili","year":"2008","journal-title":"Bioinformatics"},{"key":"2025032407032926800_r23","doi-asserted-by":"crossref","first-page":"226","DOI":"10.3390\/ijms12010226","article-title":"Computational docking of antibody-antigen complexes, opportunities and pitfalls illustrated by influenza hemagglutinin","volume":"12","author":"Pedotti","year":"2011","journal-title":"Int. J. Mol. Sci."},{"key":"2025032407032926800_r24","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1006\/meth.1999.0921","article-title":"Antibody modeling: implications for engineering and design","volume":"20","author":"Morea","year":"2000","journal-title":"Methods"},{"key":"2025032407032926800_r25","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1002\/prot.23130","article-title":"Antibody modeling assessment","volume":"79","author":"Almagro","year":"2011","journal-title":"Proteins"},{"key":"2025032407032926800_r26","doi-asserted-by":"crossref","first-page":"4990","DOI":"10.1182\/blood.V87.12.4990.bloodjournal87124990","article-title":"National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment","volume":"87","author":"Cheson","year":"1996","journal-title":"Blood"},{"key":"2025032407032926800_r27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/jmr.647","article-title":"IMGT standardized criteria for statistical analysis of immunoglobulin V-REGION amino acid properties","volume":"17","author":"Pommi\u00e9","year":"2004","journal-title":"J. Mol. Recognit."},{"key":"2025032407032926800_r28","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1038\/leu.2012.3","article-title":"Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications","volume":"26","author":"Bikos","year":"2012","journal-title":"Leukemia"},{"key":"2025032407032926800_r29","doi-asserted-by":"crossref","first-page":"D1230","DOI":"10.1093\/nar\/gkr806","article-title":"A database of immunoglobulins with integrated tools: DIGIT","volume":"40","author":"Chailyan","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2025032407032926800_r30","doi-asserted-by":"crossref","first-page":"3370","DOI":"10.1093\/nar\/gkg571","article-title":"LGA: A method for finding 3D similarities in protein structures","volume":"31","author":"Zemla","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"2025032407032926800_r31","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1006\/jmbi.1997.1354","article-title":"Standard conformations for the canonical structures of immunoglobulins","volume":"273","author":"Al-Lazikani","year":"1997","journal-title":"J. Mol. Biol."},{"key":"2025032407032926800_r32","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0377-0427(87)90125-7","article-title":"Silhouettes: a graphical aid to the interpretation and validation of cluster analysis","volume":"20","author":"Rousseeuw","year":"1987","journal-title":"J. Comput. Appl. Math."},{"key":"2025032407032926800_r33","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1002\/prot.20264","article-title":"Scoring function for automated assessment of protein structure template quality","volume":"57","author":"Zhang","year":"2004","journal-title":"Proteins"},{"key":"2025032407032926800_r34","volume-title":"Cluster Analysis for Applications.","author":"Anderberg","year":"1973"},{"key":"2025032407032926800_r35","doi-asserted-by":"crossref","first-page":"10037","DOI":"10.1073\/pnas.181342398","article-title":"Electrostatics of nanosystems: application to microtubules and the ribosome","volume":"98","author":"Baker","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032407032926800_r36","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1093\/bioinformatics\/14.9.755","article-title":"Profile hidden Markov models","volume":"14","author":"Eddy","year":"1998","journal-title":"Bioinformatics"},{"key":"2025032407032926800_r37","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1093\/bioinformatics\/btl158","article-title":"Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences","volume":"22","author":"Li","year":"2006","journal-title":"Bioinformatics"},{"key":"2025032407032926800_r38","doi-asserted-by":"crossref","first-page":"5082","DOI":"10.1021\/jo052659z","article-title":"Shapes of antibody binding sites: qualitative and quantitative analyses based on a geomorphic classification scheme","volume":"71","author":"Lee","year":"2006","journal-title":"J. Org. Chem."},{"key":"2025032407032926800_r39","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1006\/jmbi.1996.0548","article-title":"Antibody-antigen interactions: contact analysis and binding site topography","volume":"262","author":"MacCallum","year":"1996","journal-title":"J. Mol. Biol."},{"key":"2025032407032926800_r40","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":"2025032407032926800_r41","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":"Herv\u00e9","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2025032407032926800_r42","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1182\/blood-2006-10-051110","article-title":"Comprehensive characterization of IGHV3-21-expressing B-cell chronic lymphocytic leukemia: an Italian multicenter study","volume":"109","author":"Bomben","year":"2007","journal-title":"Blood"},{"key":"2025032407032926800_r43","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S0022-2836(02)01222-6","article-title":"Analysis of the antigen combining site: correlations between length and sequence composition of the hypervariable loops and the nature of the antigen","volume":"325","author":"Collis","year":"2003","journal-title":"J. Mol. Biol."},{"key":"2025032407032926800_r44","doi-asserted-by":"crossref","first-page":"665","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."},{"key":"2025032407032926800_r45","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1111\/j.1365-2141.2008.07469.x","article-title":"Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: results from an Italian multicentre study","volume":"144","author":"Bomben","year":"2009","journal-title":"Br. J. Haematol."},{"key":"2025032407032926800_r46","doi-asserted-by":"crossref","first-page":"5122","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":"2025032407032926800_r47","doi-asserted-by":"crossref","first-page":"1992","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":"2025032407032926800_r48","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1182\/blood.V99.6.2262","article-title":"Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia","volume":"99","author":"Tobin","year":"2002","journal-title":"Blood"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/190\/11\/5771\/62503224\/1300321.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/190\/11\/5771\/62503224\/1300321.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T09:20:57Z","timestamp":1742980857000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/190\/11\/5771\/8001858"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,1]]},"references-count":48,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2013,6,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1300321","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,6]]},"published":{"date-parts":[[2013,6,1]]}}}