Journal article

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

  • Agathangelidis, Andreas Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
  • Chatzidimitriou, Anastasia Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece - Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
  • 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
  • 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
  • Karypidou, Maria Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
  • 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
  • Davis, Zadie Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK
  • Yan, Xiao-Jie The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
  • Jeromin, Sabine MLL Munich Leukemia Laboratory, Munich, Germany
  • Schneider, Christof University Hospital Medical Center, Ulm, Germany
  • Bredo-Pedersen, Lone Deparment of Hematology, Rigshospitalet, Copenhagen University Hospital, Denmark
  • Tschumper, Renee C. Department of Immunology, Mayo Clinic, Rochester, MN, USA
  • Sutton, Lesley-Ann Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
  • Baliakas, Panagiotis Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden
  • 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
  • van Gastel, Ellen J. Department of Immunology, Laboratory Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
  • Armand, Marine AP-HP, Hôpital Pitié-Salpêtrière, Department of Biological Hematology, Sorbonne Université, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
  • Tausch, Eugen Department of Internal Medicine III, Ulm University, Germany
  • Biderman, Bella National Research Center for Hematology, Moscow, Russia
  • Baer, Constance MLL Munich Leukemia Laboratory, Munich, Germany
  • Bagnara, Davide Department of Experimental Medicine, University of Genoa, Italy
  • Navarro, Alba Centro de Investigacion Biomedica en Red en Oncologia (CIBERONC), Madrid, Spain - Institut d’Investigacions Biomediques August Pi I Sunyer, Barcelona, Spain
  • 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
  • Guido, Valentina Molecular Pathology Unit and Haematology Department, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy
  • Mitterbauer-Hohendanner, Gerlinde Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
  • Dimovski, Aleksandar Faculty of Pharmacy, Ss Cyril and Methodius University of Skopje, Republic of Northern Macedonia
  • Brieghel, Christian Deparment of Hematology, Rigshospitalet, Copenhagen University Hospital, Denmark
  • Lawless, Sarah Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
  • Meggendorfer, Manja MLL Munich Leukemia Laboratory, Munich, Germany
  • 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
  • Ritgen, Matthias Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Germany
  • Facco, Monica Department of Medicine-DIMED, Hematology and Clinical Immunology Unit, University of Padua, Italy - Veneto Institute of Molecular Medicine, Padua, Italy
  • Tresoldi, Cristina Division of Immunology, Transplantation and Infectious, IRCCS San Raffaele Scientific Institute, Milan, Italy
  • Visentin, Andrea Department of Medicine-DIMED, Hematology and Clinical Immunology Unit, University of Padua, Italy - Veneto Institute of Molecular Medicine, Padua, Italy
  • Patriarca, Andrea Division of Immunology, Transplantation and Infectious, IRCCS San Raffaele Scientific Institute, Milan, Italy
  • Catherwood, Mark Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
  • Bonello, Lisa General Anatomopathology and Molecular Oncogenetics - AOU City of Health and Science of Turin, Italy
  • Sudarikov, Andrey National Research Center for Hematology, Moscow, Russia
  • Vanura, Katrina Department of Laboratory Medicine, Medical University of Vienna, Austria
  • Roumelioti, Maria First Department of Propaedeutic Medicine, University of Athens, Greece
  • Skuhrova-Francova, Hana Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Czech Republic
  • Moysiadis, Theodoros Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
  • Veronese, Silvio Molecular Pathology Unit and Haematology Department, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy
  • Giannopoulos, Krzysztof Experimental Hematooncology Department, Medical University of Lublin, Poland
  • Mansouri, Larry Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
  • Karan-Djurasevic, Teodora Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Serbia
  • Sandaltzopoulos, Raphael Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
  • Bödör, Csaba MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
  • Fais, Franco Department of Experimental Medicine, University of Genoa, Italy - U.O. Molecular Pathology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
  • Kater, Arnon Amsterdam UMC, University of Amsterdam, Department of Hematology, Amsterdam Infection and Immunity Institute, Cancer Center Amsterdam, the Netherlands
  • Panovska, Irina Department of Hematology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje Republic of Northern Macedonia
  • Rossi, Davide Division of Hematology, Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Alshemmari, Salem Department of Medicine, Faculty of Medicine, Kuwait University, Safat, Kuwait
  • Panagiotidis, Panagiotis First Department of Propaedeutic Medicine, University of Athens, Greece
  • Costeas, Paul The Center for the Study of Haematological Malignancies, Nicosia, Cyprus - Karaiskakio Foundation, Nicosia, Cyprus
  • Espinet Solà, Blanca Laboratorio de Citogenètica Molecular, Laboratori de Citologia Hematològica, Servei de Patologia i Servei de Hematologia, Hospital del Mar, Barcelona, Spain
  • Antic, Darko Clinic for Hematology, Clinical Center of Serbia, Belgrade, Serbia
  • Foroni, Letizia Hammersmith Hospital, London, UK
  • Montillo, Marco Molecular Pathology Unit and Haematology Department, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy
  • Trentin, Livio Department of Medicine-DIMED, Hematology and Clinical Immunology Unit, University of Padua, Italy - Veneto Institute of Molecular Medicine, Padua, Italy
  • Stavroyianni, Niki Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
  • Gaidano, Gianluca Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont and Ospedale Maggiore della Carità, Novara, Italy
  • Francia di Celle, Paola General Anatomopathology and Molecular Oncogenetics - AOU City of Health and Science of Turin, Italy
  • Niemann, Carsten Deparment of Hematology, Rigshospitalet, Copenhagen University Hospital, Denmark
  • 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
  • Anagnostopoulos, Achilles Hammersmith Hospital, London, UK
  • Pott, Christiane Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Germany
  • Fischer, Kirsten University Hospital Cologne, Germany
  • Hallek, Michael University of Cologne, Germany
  • Oscier, David Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK
  • Stilgenbauer, Stephan Department of Internal Medicine III, Ulm University, Ulm, Germany
  • Haferlach, Claudia MLL Munich Leukemia Laboratory, Munich, Germany
  • Jelinek, Diane Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA
  • Chiorazzi, Nicholas The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
  • 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
  • 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
  • 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
  • Langerak, Anton W. Department of Immunology, Laboratory Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
  • Belessi, Chrysoula Hematology Department, Nikea General Hospital, Pireaus, Greece
  • Davi, Frederic Department of Immunology, Laboratory Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
  • Rosenquist, Richard Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden - Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
  • 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
  • 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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    29.09.2020
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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