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Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL
A. Agathangelidis, A. Chatzidimitriou, K. Gemenetzi, V. Giudicelli, M. Karypidou, K. Plevova, Z. Davis, XJ. Yan, S. Jeromin, C. Schneider, LB. Pedersen, RC. Tschumper, LA. Sutton, P. Baliakas, L. Scarfò, EJ. van Gastel, M. Armand, E. Tausch, B....
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
R01 CA238523
NCI NIH HHS - United States
NLK
Free Medical Journals
from 1946 to 1 year ago
Freely Accessible Science Journals
from 1946 to 1 year ago
Open Access Digital Library
from 1946-01-01
Open Access Digital Library
from 1946-01-01
ROAD: Directory of Open Access Scholarly Resources
- MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell genetics MeSH
- Gene Frequency MeSH
- Gene Rearrangement MeSH
- Humans MeSH
- Somatic Hypermutation, Immunoglobulin MeSH
- Immunoglobulin Heavy Chains genetics MeSH
- Immunoglobulin Variable Region genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
1st Department of Propaedeutic Medicine University of Athens Athens Greece
2nd Medical Department University Hospital Schleswig Holstein Campus Kiel Kiel Germany
Centro de Investigacion Biomedica en Red en Oncologia Madrid Spain
Clinic for Hematology Clinical Center of Serbia Belgrade Serbia
Clinical Genetics Karolinska University Laboratory Karolinska University Hospital Stockholm Sweden
Deparment of Hematology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark
Department 1 of Internal Medicine University of Cologne Cologne Germany
Department of Experimental Medicine University of Genoa Genoa Italy
Department of Haematology Royal Bournemouth Hospital Bournemouth United Kingdom
Department of Immunology Mayo Clinic Rochester MN
Department of Immunology Mayo Clinic Scottsdale AZ
Department of Internal Medicine 3 Ulm University Ulm Germany
Department of Laboratory Medicine Medical University of Vienna Vienna Austria
Department of Medicine Faculty of Medicine Kuwait University Safat Kuwait
Department of Molecular Biology and Genetics Democritus University of Thrace Alexandroupolis Greece
Department of Molecular Medicine and Surgery Karolinska Institute Stockholm Sweden
Division of Hematology Oncology Institute of Southern Switzerland Bellinzona Switzerland
Experimental Hematooncology Department Medical University of Lublin Lublin Poland
Hammersmith Hospital London United Kingdom
Hematocrit Unit Hematology Department G Papanicolaou Hospital Thessaloniki Greece
Hematology and Clinical Immunology Unit Department of Medicine University of Padua Padua Italy
Hematology Department Nikea General Hospital Pireaus Greece
Hospital Clinic of Barcelona University of Barcelona Barcelona Spain
Institut d'Investigacions Biomediques August Pi 1 Sunyer Barcelona Spain
Institute of Applied Biosciences Centre for Research and Technology Hellas Thessaloniki Greece
Institute of Molecular Genetics and Genetic Engineering University of Belgrade Belgrade Serbia
International ImMunoGeneTics Information System Université de Montpellier Montpellier France
Karaiskakio Foundation Nicosia Cyprus
MLL Munich Leukemia Laboratory Munich Germany
Molecular Pathology Unit Haematology Department Niguarda Cancer Center Niguarda Hospital Milan Italy
National Research Center for Hematology Moscow Russia
The Center for the Study of Haematological Malignancies Nicosia Cyprus
The Feinstein Institute for Medical Research Northwell Health Manhasset NY
University Hospital Cologne Cologne Germany
University Hospital Medical Center Ulm Germany
UO Molecular Pathology IRCCS Ospedale Policlinico San Martino Genoa Italy
References provided by Crossref.org
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