Higher-order connections between stereotyped subsets

Agathangelidis, Andreas; Chatzidimitriou, Anastasia; Gemenetzi, Katerina; Giudicelli, Veronique; Karypidou, Maria; Plevova, Karla; Davis, Zadie; Yan, Xiao-Jie; Jeromin, Sabine; Schneider, Christof; Bredo-Pedersen, Lone; 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; Braazdilova, 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 Solà, 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

doi:10.1182/blood.2020007039

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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

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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