Higher-order connections between stereotyped subsets : implications for improved patient classification in CLL
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Agathangelidis, Andreas
Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
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Chatzidimitriou, Anastasia
Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece - Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
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Gemenetzi, Katerina
Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece - Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
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Giudicelli, Veronique
IMGT®, The International ImMunoGeneTics Information System®, Laboratoire d'ImmunoGénétique Moléculaire (LIGM), Institut de Génétique Humaine (IGH), UMR 9002 CNRS-UM, Université de Montpellier, France
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Karypidou, Maria
Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
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Plevova, Karla
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Czech Republic - Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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Davis, Zadie
Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK
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Yan, Xiao-Jie
The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
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Jeromin, Sabine
MLL Munich Leukemia Laboratory, Munich, Germany
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Schneider, Christof
University Hospital Medical Center, Ulm, Germany
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Bredo-Pedersen, Lone
Deparment of Hematology, Rigshospitalet, Copenhagen University Hospital, Denmark
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Tschumper, Renee C.
Department of Immunology, Mayo Clinic, Rochester, MN, USA
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Sutton, Lesley-Ann
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
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Baliakas, Panagiotis
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden
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Scarfò, Lydia
Strategic Research Program on CLL and B-cell neoplasia Unit, Division of Experimental Oncology, Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy
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van Gastel, Ellen J.
Department of Immunology, Laboratory Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
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Armand, Marine
AP-HP, Hôpital Pitié-Salpêtrière, Department of Biological Hematology, Sorbonne Université, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
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Tausch, Eugen
Department of Internal Medicine III, Ulm University, Germany
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Biderman, Bella
National Research Center for Hematology, Moscow, Russia
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Baer, Constance
MLL Munich Leukemia Laboratory, Munich, Germany
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Bagnara, Davide
Department of Experimental Medicine, University of Genoa, Italy
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Navarro, Alba
Centro de Investigacion Biomedica en Red en Oncologia (CIBERONC), Madrid, Spain - Institut d’Investigacions Biomediques August Pi I Sunyer, Barcelona, Spain
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Langlois de Septenville, Anne
AP-HP, Hôpital Pitié-Salpêtrière, Department of Biological Hematology, Sorbonne Université, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
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Guido, Valentina
Molecular Pathology Unit and Haematology Department, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy
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Mitterbauer-Hohendanner, Gerlinde
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
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Dimovski, Aleksandar
Faculty of Pharmacy, Ss Cyril and Methodius University of Skopje, Republic of Northern Macedonia
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Brieghel, Christian
Deparment of Hematology, Rigshospitalet, Copenhagen University Hospital, Denmark
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Lawless, Sarah
Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
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Meggendorfer, Manja
MLL Munich Leukemia Laboratory, Munich, Germany
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Braazdilova, Kamila
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Czech Republic - Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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Ritgen, Matthias
Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Germany
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Facco, Monica
Department of Medicine-DIMED, Hematology and Clinical Immunology Unit, University of Padua, Italy - Veneto Institute of Molecular Medicine, Padua, Italy
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Tresoldi, Cristina
Division of Immunology, Transplantation and Infectious, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Visentin, Andrea
Department of Medicine-DIMED, Hematology and Clinical Immunology Unit, University of Padua, Italy - Veneto Institute of Molecular Medicine, Padua, Italy
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Patriarca, Andrea
Division of Immunology, Transplantation and Infectious, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Catherwood, Mark
Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
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Bonello, Lisa
General Anatomopathology and Molecular Oncogenetics - AOU City of Health and Science of Turin, Italy
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Sudarikov, Andrey
National Research Center for Hematology, Moscow, Russia
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Vanura, Katrina
Department of Laboratory Medicine, Medical University of Vienna, Austria
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Roumelioti, Maria
First Department of Propaedeutic Medicine, University of Athens, Greece
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Skuhrova-Francova, Hana
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Czech Republic
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Moysiadis, Theodoros
Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
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Veronese, Silvio
Molecular Pathology Unit and Haematology Department, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy
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Giannopoulos, Krzysztof
Experimental Hematooncology Department, Medical University of Lublin, Poland
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Mansouri, Larry
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
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Karan-Djurasevic, Teodora
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Serbia
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Sandaltzopoulos, Raphael
Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
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Bödör, Csaba
MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
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Fais, Franco
Department of Experimental Medicine, University of Genoa, Italy - U.O. Molecular Pathology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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Kater, Arnon
Amsterdam UMC, University of Amsterdam, Department of Hematology, Amsterdam Infection and Immunity Institute, Cancer Center Amsterdam, the Netherlands
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Panovska, Irina
Department of Hematology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje Republic of Northern Macedonia
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Rossi, Davide
Division of Hematology, Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Alshemmari, Salem
Department of Medicine, Faculty of Medicine, Kuwait University, Safat, Kuwait
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Panagiotidis, Panagiotis
First Department of Propaedeutic Medicine, University of Athens, Greece
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Costeas, Paul
The Center for the Study of Haematological Malignancies, Nicosia, Cyprus - Karaiskakio Foundation, Nicosia, Cyprus
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Espinet Solà, Blanca
Laboratorio de Citogenètica Molecular, Laboratori de Citologia Hematològica, Servei de Patologia i Servei de Hematologia, Hospital del Mar, Barcelona, Spain
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Antic, Darko
Clinic for Hematology, Clinical Center of Serbia, Belgrade, Serbia
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Foroni, Letizia
Hammersmith Hospital, London, UK
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Montillo, Marco
Molecular Pathology Unit and Haematology Department, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy
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Trentin, Livio
Department of Medicine-DIMED, Hematology and Clinical Immunology Unit, University of Padua, Italy - Veneto Institute of Molecular Medicine, Padua, Italy
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Stavroyianni, Niki
Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
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Gaidano, Gianluca
Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont and Ospedale Maggiore della Carità, Novara, Italy
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Francia di Celle, Paola
General Anatomopathology and Molecular Oncogenetics - AOU City of Health and Science of Turin, Italy
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Niemann, Carsten
Deparment of Hematology, Rigshospitalet, Copenhagen University Hospital, Denmark
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Campo, Elias
Centro de Investigacion Biomedica en Red en Oncologia (CIBERONC), Madrid, Spain - Institut d’Investigacions Biomediques August Pi I Sunyer, Barcelona, Spain - Hospital Clinic of Barcelona, University of Barcelona, Spain
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Anagnostopoulos, Achilles
Hammersmith Hospital, London, UK
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Pott, Christiane
Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Germany
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Fischer, Kirsten
University Hospital Cologne, Germany
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Hallek, Michael
University of Cologne, Germany
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Oscier, David
Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK
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Stilgenbauer, Stephan
Department of Internal Medicine III, Ulm University, Ulm, Germany
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Haferlach, Claudia
MLL Munich Leukemia Laboratory, Munich, Germany
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Jelinek, Diane
Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA
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Chiorazzi, Nicholas
The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
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Pospisilova, Sarka
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Czech Republic - Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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Lefranc, Marie-Paule
IMGT®, The International ImMunoGeneTics Information System®, Laboratoire d'ImmunoGénétique Moléculaire (LIGM), Institut de Génétique Humaine (IGH), UMR 9002 CNRS-UM, Université de Montpellier, France
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Kossida, Sofia
IMGT®, The International ImMunoGeneTics Information System®, Laboratoire d'ImmunoGénétique Moléculaire (LIGM), Institut de Génétique Humaine (IGH), UMR 9002 CNRS-UM, Université de Montpellier, France
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Langerak, Anton W.
Department of Immunology, Laboratory Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
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Belessi, Chrysoula
Hematology Department, Nikea General Hospital, Pireaus, Greece
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Davi, Frederic
Department of Immunology, Laboratory Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
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Rosenquist, Richard
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden - Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
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Ghia, Paolo
Strategic Research Program on CLL and B-cell neoplasia Unit, Division of Experimental Oncology, Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy
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Stamatopoulos, Kostas
Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece - Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
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Published in:
- Blood. - 2020, vol. 137, no. 10, p. 1365–1376
English
Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B cell receptor immunoglobulins (BcR IG). Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR IG 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 IG stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. In order 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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https://n2t.net/ark:/12658/srd1319269
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