Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: A molecular classification with implications for targeted therapies

Andreas Agathangelidis, Nikos Darzentas, Anastasia Hadzidimitriou, Xavier Brochet, Fiona Murray, Xiao Jie Yan, Zadie Davis, Ellen J. Van Gastel-Mol, Cristina Tresoldi, Charles C. Chu, Nicola Cahill, Veronique Giudicelli, Boris Tichy, Lone Bredo Pedersen, Letizia Foroni, Lisa Bonello, Agnieszka Janus, Karin Smedby, Achilles Anagnostopoulos, Helene Merle-BeralNikolaos Laoutaris, Gunnar Juliusson, Paola Francia Di Celle, Sarka Pospisilova, Jesper Jurlander, Christian Geisler, Athanasios Tsaftaris, Marie Paule Lefranc, Anton W. Langerak, David Graham Oscier, Nicholas Chiorazzi, Chrysoula Belessi, Frederic Davi, Richard Rosenquist, Paolo Ghia, Kostas Stamatopoulos

Research output: Contribution to journalArticle

Abstract

Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination ofVHsequencesmaypave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.

Original languageEnglish
Pages (from-to)4467-4475
Number of pages9
JournalBlood
Volume119
Issue number19
DOIs
Publication statusPublished - May 10 2012

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Agathangelidis, A., Darzentas, N., Hadzidimitriou, A., Brochet, X., Murray, F., Yan, X. J., Davis, Z., Van Gastel-Mol, E. J., Tresoldi, C., Chu, C. C., Cahill, N., Giudicelli, V., Tichy, B., Pedersen, L. B., Foroni, L., Bonello, L., Janus, A., Smedby, K., Anagnostopoulos, A., ... Stamatopoulos, K. (2012). Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: A molecular classification with implications for targeted therapies. Blood, 119(19), 4467-4475. https://doi.org/10.1182/blood-2011-11-393694