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

ERIC, the European Research Initiative on 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 C. Tschumper, Lesley Ann Sutton, Panagiotis Baliakas, Lydia Scarfò, Ellen J. van Gastel, Marine Armand, Eugen Tausch, Bella BidermanConstance 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, Kirsten Fischer, Anton W. Langerak

Research output: Contribution to journalArticleAcademicpeer-review

61 Citations (Scopus)


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. Key Points: • In a series of 29 856 CLL patients, the incidence of BcR stereotypy peaked at 41%. • Higher-order relations exist between stereotyped subsets, particularly for those from U-CLL, for which satellite subsets were identified.

Original languageEnglish
Pages (from-to)1365-1376
Number of pages12
Issue number10
Publication statusPublished - 11 Mar 2021

Bibliographical note

Funding Information:
Conflict-of-interest disclosure: S.V. has received honoraria from Bayer, AstraZeneca, and Janssen; A.K. has received research funding from AbbVie, Roche/Genentech, Janssen, and AstraZeneca. D.R. has received honoraria from AbbVie, AstraZeneca, Gilead, Janssen, Verastem, and research grants from AbbVie, Gilead, Janssen, and Cellestia. S.A. has received educational grants from Johnson & Johnson, AbbVie, and Roche. K. Giannopoulos has received honoraria from AbbVie, Janssen, and Roche. L.T. has received honoraria from AbbVie, Roche, Janssen, and Shire. A.V. has received honoraria from Janssen and AbbVie. G.G. has received honoraria from AbbVie, Janssen, Sunesis, and AstraZeneca for advisory boards or speaker's bureau services. C.N. has received research support, consultancy fees, and/or travel grants from AbbVie, Gilead, Janssen, Roche, CSL Behring, Genmab, Sunesis, and Acerta/AstraZeneca outside this work. K.F. has received honoraria from Roche and AbbVie, and Roche travel grants. S.S. has received honoraria and research support from AbbVie, AstraZeneca, Celgene, Gilead, GlaxoSmithKline, Hoffmann La-Roche, Janssen, and Novartis. R.R. has received honoraria from AbbVie, Illumina, Janssen, and Roche. P.G. has received honoraria from AbbVie, Acerta, BeiGene, Gilead, Janssen, Sunesis, and reseach funding from AbbVie, Gilead, Janssen, Novartis, and Sunesis. K.S. has received honoraria and research support from AbbVie, Janssen, AstraZeneca, and Gilead. The remaining authors declare no competing financial interests.

Funding Information:
This work was supported by the Hellenic Foundation for Research and Innovation (HFRI) and the General Secretariat for Research and Technology (GSRT), under grant agreement no. 336 (Project CLLon); the Hellenic Precision Medicine Network in Oncology; the Swedish Cancer Society; the Swedish Research Council; the Knut and Alice Wallenberg Foundation; Karolinska Institutet; Karolinska University Hospital; Radiumhemmets Forskningsfonder, Stockholm; German Research Foundation (DFG) subprojects B1 and B2 of SFB1074; the Bournemouth Leukaemia Fund; the Kuwait Foundation for Advancement of Sciences (KFAS; research grant PR1713MM03); the Polish Scientific Centre (NCN 2018/29/B/NZ5/02706); the Swiss Cancer League (ID 3746, 4395 4660, and 4705); the European Research Council (ERC) Consolidator Grant CLLCLONE (ID 772051); the Swiss National Science Foundation (ID 320030_169670/1 and 310030_192439), Bern, Switzerland; the Leukemia & Lymphoma Society, Translational Research Program (ID 6594-20); the Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG 15426), the European Union's Horizon 2020 Research and Innovation Programme under 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 Northern Ireland (NI); the AIRC Milan Project (IG 15397), Grant MH-CZ AZV NV19-03-00091, Project NPUII MEYSCZ (CEITEC2020 LQ1601); University Hospital Brno Project (MH-CZ RVO 65269705); AIRC 5 × 1000 (grant 21198); and the Novo Nordisk Foundation (grant NNF16OC0019302).

Publisher Copyright:
© 2021 American Society of Hematology


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