Stereotyped B-cell receptors in one third of chronic lymphocytic leukemia: towards a molecular classification with implications for targeted therapeutic interventions

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-Beral, Nikolaos 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 and Kostas Stamatopoulos


Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped B cell receptors (BcR) 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 immunoglobulin (IG) stereotypes. To this end, we examined 7596 IG VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, three 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 two distinct categories: one with stereotyped and the other with non-stereotyped BcRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these two 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 of VH sequences may pave the way towards a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.

  • Submitted November 28, 2011.
  • Accepted February 26, 2012.