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Rigshospitalet - a part of Copenhagen University Hospital
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Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

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

Original languageEnglish
JournalBlood
Volume137
Issue number10
Pages (from-to)1365-1376
Number of pages12
ISSN0006-4971
DOIs
Publication statusPublished - 11 Mar 2021

ID: 62290906