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Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL.

ABSTRACT: 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.

SUBMITTER: Agathangelidis A

PROVIDER: S-EPMC7976441 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL.

Agathangelidis Andreas A Chatzidimitriou Anastasia A Gemenetzi Katerina K Giudicelli Veronique V Karypidou Maria M Plevova Karla K Davis Zadie Z Yan Xiao-Jie XJ Jeromin Sabine S Schneider Christof C Pedersen Lone Bredo LB Tschumper Renee C RC Sutton Lesley-Ann LA Baliakas Panagiotis P Scarfò Lydia L van Gastel Ellen J EJ Armand Marine M Tausch Eugen E Biderman Bella B Baer Constance C Bagnara Davide D Navarro Alba A Langlois de Septenville Anne A Guido Valentina V Mitterbauer-Hohendanner Gerlinde G Dimovski Aleksandar A Brieghel Christian C Lawless Sarah S Meggendorfer Manja M Brazdilova Kamila K Ritgen Matthias M Facco Monica M Tresoldi Cristina C Visentin Andrea A Patriarca Andrea A Catherwood Mark M Bonello Lisa L Sudarikov Andrey A Vanura Katrina K Roumelioti Maria M Skuhrova Francova Hana H Moysiadis Theodoros T Veronese Silvio S Giannopoulos Krzysztof K Mansouri Larry L Karan-Djurasevic Teodora T Sandaltzopoulos Raphael R Bödör Csaba C Fais Franco F Kater Arnon P AP Panovska Irina I Rossi Davide D Alshemmari Salem S Panagiotidis Panagiotis P Costeas Paul P Espinet Blanca B Antic Darko D Foroni Letizia L Montillo Marco M Trentin Livio L Stavroyianni Niki N Gaidano Gianluca G Francia di Celle Paola P Niemann Carsten C Campo Elias E Anagnostopoulos Achilles A Pott Christiane C Fischer Kirsten K Hallek Michael M Oscier David D Stilgenbauer Stephan S Haferlach Claudia C Jelinek Diane D Chiorazzi Nicholas N Pospisilova Sarka S Lefranc Marie-Paule MP Kossida Sofia S Langerak Anton W AW Belessi Chrysoula C Davi Frederic F Rosenquist Richard R Ghia Paolo P Stamatopoulos Kostas K

Blood 20210301 10

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, especial ...[more]

PMID: 32992344

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Project description:BackgroundB cell receptor Immunoglobulin (BcR IG) repertoire of Chronic Lymphocytic Leukemia (CLL) is characterized by the expression of quasi-identical BcR IG. These are observed in approximately 30% of patients, defined as stereotyped receptors and subdivided into subsets based on specific VH CDR3 aa motifs and phylogenetically related IGHV genes. Although relevant to CLL ontogeny, the distribution of CLL-biased stereotyped immunoglobulin rearrangements (CBS-IG) in normal B cells has not been so far specifically addressed using modern sequencing technologies. Here, we have investigated the presence of CBS-IG in splenic B cell subpopulations (s-BCS) and in CD5+ and CD5- B cells from the spleen and peripheral blood (PB).MethodsFractionation of splenic B cells into 9 different B cell subsets and that of spleen and PB into CD5+ and CD5- cells were carried out by FACS sorting. cDNA sequences of BcR IG gene rearrangements were obtained by NGS. Identification of amino acidic motifs typical of CLL stereotyped subsets was carried out on IGHV1-carrying gene sequences and statistical evaluation has been subsequently performed to assess stereotypes distribution.ResultsCBS-IG represented the 0.26% average of IGHV1 genes expressing sequences, were detected in all of the BCS investigated. CBS-IG were more abundant in splenic and circulating CD5+ B (0.57%) cells compared to CD5- B cells (0.17%). In all instances, most CBS IG did not exhibit somatic hypermutation similar to CLL stereotyped receptors. However, compared to CLL, they exhibited a different CLL subset distribution and a broader utilization of the genes of the IGHV1 family.ConclusionsCBS-IG receptors appear to represent a part of the "public" BcR repertoire in normal B cells. This repertoire is observed in all BCS excluding the hypothesis that CLL stereotyped BcR accumulate in a specific B cell subset, potentially capable of originating a leukemic clone. The different relative representation of CBS-IG in normal B cell subgroups suggests the requirement for additional selective processes before a full transformation into CLL is achieved.

Dataset Information

Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL.

Publications

Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL.

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