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

Andreas Agathangelidis; Anastasia Chatzidimitriou; Katerina Gemenetzi; Veronique Giudicelli; Maria Karypidou; Karla Plevova; Zadie Davis; Xiao-Jie Yan; Sabine Jeromin; Christof Schneider; Lone Bredo Pedersen; Renee Tschumper; Lesley-Ann Sutton; Panagiotis Baliakas; Lydia Scarfò; Ellen van Gastel; Marine Armand; Eugen Tausch; Bella Biderman; Constance Baer; Davide Bagnara; Alba Navarro; Anne Langlois de Septenville; Valentina Guido; Gerlinde Mitterbauer-Hohendanner; Aleksandar Dimovski; Christian Brieghel; Sarah Lawless; Manja Meggendorfer; Kamila Brazdilova; 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 Veronese; Krzysztof Giannopoulos; Larry Mansouri; Teodora Karan-Djurasevic; Raphael Sandaltzopoulos; Csaba Bödör; Franco Fais; Arnon Kater; Irina Panovska; Davide Rossi; Salem Alshemmari; Panagiotis Panagiotidis; Paul Costeas; Blanca Espinet; Darko Antic; Letizia Foroni; Marco Montillo; Livio Trentin; Niki Stavroyianni; Gianluca Gaidano; Paola Francia Di Celle; Carsten Niemann; Elias Campo; Achilles Anagnostopoulos; Christiane Pott; Kirsten Fischer; Michael Hallek; David Oscier; Stephan Stilgenbauer; Claudia Haferlach; Diane Jelinek; Nicholas Chiorazzi; Sarka Pospisilova; Marie-Paule Lefranc; Sofia Kossida; Anton Langerak; Chrysoula Belessi; Frederic Davi; Richard Rosenquist; Paolo Ghia; Kostas Stamatopoulos

doi:10.1182/blood.2020007039

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

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

Andreas Agathangelidis, Anastasia Chatzidimitriou, Katerina Gemenetzi, Veronique Giudicelli, Maria Karypidou, Karla Plevova, Zadie Davis, Xiao-Jie Yan, Sabine Jeromin, Christof Schneider, …

Blood, Vol.137(10), pp.1365-1376

11/03/2021

DOI: https://doi.org/10.1182/blood.2020007039

PMCID: PMC7976441

PMID: 32992344

Abstract

Gene Frequency

Gene Rearrangement

Humans

Immunoglobulin Heavy Chains

Immunoglobulin Variable Region

Leukemia, Lymphocytic, Chronic, B-Cell

Somatic Hypermutation, Immunoglobulin

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.

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Title: Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL
Creators - without role: Andreas Agathangelidis - Centre for Research and Technology Hellas
Anastasia Chatzidimitriou - Centre for Research and Technology Hellas
Katerina Gemenetzi - Centre for Research and Technology Hellas
Veronique Giudicelli - Université de Montpellier, Institut de Génétique Humaine - IGH
Maria Karypidou - Centre for Research and Technology Hellas
Karla Plevova - Masaryk University
Zadie Davis - Royal Bournemouth Hospital
Xiao-Jie Yan - Feinstein Institute for Medical Research
Sabine Jeromin - Munich Leukemia Laboratory
Christof Schneider - University Hospital Ulm
Lone Bredo Pedersen - Copenhagen University Hospital
Renee Tschumper - Mayo Clinic in Arizona
Lesley-Ann Sutton - Karolinska Institutet
Panagiotis Baliakas - Uppsala University
Lydia Scarfò - Vita-Salute San Raffaele University
Ellen van Gastel - Erasmus MC
Marine Armand - Centre de Recherche des Cordeliers
Eugen Tausch - Universität Ulm
Bella Biderman - Federal State Institution Hematology Research Center
Constance Baer - Munich Leukemia Laboratory
Davide Bagnara - University of Genoa
Alba Navarro - Centro de Investigación Biomédica en Red de Cáncer
Anne Langlois de Septenville
Valentina Guido - Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
Gerlinde Mitterbauer-Hohendanner - Medical University of Vienna
Aleksandar Dimovski - Saints Cyril and Methodius University of Skopje
Christian Brieghel - Copenhagen University Hospital
Sarah Lawless - Belfast Health and Social Care Trust
Manja Meggendorfer - Munich Leukemia Laboratory
Kamila Brazdilova - Masaryk University
Matthias Ritgen - University of Lübeck
Monica Facco - University of Padua
Cristina Tresoldi - Vita-Salute San Raffaele University
Andrea Visentin - University of Padua
Andrea Patriarca - Università degli Studi del Piemonte Orientale “Amedeo Avogadro”
Mark Catherwood - University of Ulster
Lisa Bonello - Ospedale Sant'Anna
Andrey Sudarikov - Federal State Institution Hematology Research Center
Katrina Vanura - Medical University of Vienna
Maria Roumelioti - National and Kapodistrian University of Athens
Hana Skuhrova Francova - University Hospital Brno
Theodoros Moysiadis - Centre for Research and Technology Hellas
Silvio Veronese - Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
Krzysztof Giannopoulos - Medical University of Lublin
Larry Mansouri - Karolinska Institutet
Teodora Karan-Djurasevic - University of Belgrade
Raphael Sandaltzopoulos - Democritus University of Thrace
Csaba Bödör - Semmelweis University
Franco Fais - University of Genoa
Arnon Kater - Amsterdam University Medical Centers
Irina Panovska - Saints Cyril and Methodius University of Skopje
Davide Rossi - Institute of Oncology Research
Salem Alshemmari - Kuwait University
Panagiotis Panagiotidis - National and Kapodistrian University of Athens
Paul Costeas - Center for the Study of Childhood and Adolescence
Blanca Espinet - Hospital Del Mar
Darko Antic - Centar za Promociju Nauke
Letizia Foroni - Hammersmith Hospital
Marco Montillo - Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
Livio Trentin - University of Padua
Niki Stavroyianni - G. Papanikolaou General Hospital
Gianluca Gaidano - Università degli Studi del Piemonte Orientale “Amedeo Avogadro”
Paola Francia Di Celle - Città della Salute e della Scienza di Torino
Carsten Niemann - Rigshospitalet
Elias Campo - Hospital Clínic de Barcelona
Achilles Anagnostopoulos - Hammersmith Hospital
Christiane Pott - University of Lübeck
Kirsten Fischer - University Hospital Cologne
Michael Hallek - University of Cologne
David Oscier - Royal Bournemouth Hospital
Stephan Stilgenbauer - Universität Ulm
Claudia Haferlach - Munich Leukemia Laboratory
Diane Jelinek - Mayo Clinic in Arizona
Nicholas Chiorazzi - Feinstein Institute for Medical Research
Sarka Pospisilova - Masaryk University
Marie-Paule Lefranc - Université de Montpellier, Institut de Génétique Humaine - IGH
Sofia Kossida - Université de Montpellier, Institut de Génétique Humaine - IGH
Anton Langerak - Erasmus MC
Chrysoula Belessi - General Hospital of Nikea
Frederic Davi - Erasmus MC
Richard Rosenquist - Karolinska Institutet
Paolo Ghia - IRCCS Ospedale San Raffaele
Kostas Stamatopoulos - Karolinska Institutet
Publication Details: Blood, Vol.137(10), pp.1365-1376
Grant note: This work was supported by the Hellenic Foundation for Research andInnovation (HFRI) and the General Secretariat for Research and Tech-nology (GSRT), under grant agreement no. 336 (Project CLLon); theHellenic Precision Medicine Network in Oncology; the Swedish CancerSociety; the Swedish Research Council; the Knut and Alice WallenbergFoundation; Karolinska Institutet; Karolinska University Hospital; Radi-umhemmets Forskningsfonder, Stockholm; German Research Founda-tion (DFG) subprojects B1 and B2 of SFB1074; the BournemouthLeukaemia Fund; the Kuwait Foundation for Advancement of Sciences(KFAS; research grant PR1713MM03); the Polish Scientific Centre (NCN2018/29/B/NZ5/02706); the Swiss Cancer League (ID 3746, 4395 4660,and 4705); the European Research Council (ERC) Consolidator GrantCLLCLONE (ID 772051); the Swiss National Science Foundation (ID320030_169670/1 and 310030_192439), Bern, Switzerland; the Leuke-mia & Lymphoma Society, Translational Research Program (ID 6594-20);the Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG 15426), theEuropean Union’s Horizon 2020 Research and Innovation Programmeunder the Marie Skłodowska-Curie Grant (agreement no. 794075);the Momentum Grant of the Hungarian Academy of Sciences (LP-95021);the Hungarian National Research, Development and Innovation Office(grant NVKP_16-1-2016-0004); the Leukaemia and Lymphoma NorthernIreland (NI); the AIRC Milan Project (IG 15397), Grant MH-CZ AZV NV19-03-00091, Project NPUII MEYSCZ (CEITEC2020 LQ1601); UniversityHospital Brno Project (MH-CZ RVO 65269705); AIRC 5 3 1000 (grant21198); and the Novo Nordisk Foundation (grant NNF16OC0019302).
Identifiers: 9938228209311
Academic Unit: Institut de Génétique Humaine - IGH
Language: English
Resource Type: Journal article
Local Fields: hal-04337928