Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL
Authors: Agathangelidis Andreas , Chatzidimitriou Anastasia , Gemenetzi Katerina , Giudicelli Veronique , Karypidou Maria , Plevova Karla , Davis Zadie , Yan Xiao-Jie , Jeromin Sabine , Schneider Christof , Pedersen Lone Bredo , Tschumper Renee C. , Sutton Lesley-Ann , Baliakas Panagiotis , Scarfò Lydia , van Gastel Ellen J. , Armand Marine , Tausch Eugen , Biderman Bella , Baer Constance , Bagnara Davide , Navarro Alba , Langlois de Septenville Anne , Guido Valentina , Mitterbauer-Hohendanner Gerlinde , Dimovski Aleksandar , Brieghel Christian , Lawless Sarah , Meggendorfer Manja , Brazdilova Kamila , Ritgen Matthias , Facco Monica , Tresoldi Cristina , Visentin Andrea , Patriarca Andrea , Catherwood Mark , Bonello Lisa , Sudarikov Andrey , Vanura Katrina , Roumelioti Maria , Skuhrova Francova Hana , Moysiadis Theodoros , Veronese Silvio , Giannopoulos Krzysztof , Mansouri Larry , Karan-Djurasevic Teodora , Sandaltzopoulos Raphael , Bödör Csaba , Fais Franco , Kater Arnon , Panovska Irina , Rossi Davide , Alshemmari Salem , Panagiotidis Panagiotis , Costeas Paul , Espinet Blanca , Antic Darko , Foroni Letizia , Montillo Marco , Trentin Livio , Stavroyianni Niki , Gaidano Gianluca , Francia di Celle Paola , Niemann Carsten , Campo Elias , Anagnostopoulos Achilles , Pott Christiane , Fischer Kirsten , Hallek Michael , Oscier David , Stilgenbauer Stephan , Haferlach Claudia , Jelinek Diane , Chiorazzi Nicholas , Pospisilova Sarka , Lefranc Marie-Paule , Kossida Sofia , Langerak Anton W. , Belessi Chrysoula , Davi Frederic , Rosenquist Richard , Ghia Paolo , Stamatopoulos Kostas 
Published: September 2020

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.