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

Agathangelidis, Andreas; Darzentas, Nikos; Hadzidimitriou, Anastasia; Brochet, Xavier; Murray, Fiona; Yan, Xiao-Jie; Davis, Zadie; van Gastel-Mol, Ellen J.; Tresoldi, Cristina and Chu, Charles C., et al. (2012) In Blood 119(19). p.4467-4475
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... (More)
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 of VH sequences may pave 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. (Blood. 2012;119(19):4467-4475) (Less)
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@article{90c0f1fa-6017-4bcb-a62d-667f8f4dab02,
  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 of VH sequences may pave 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. (Blood. 2012;119(19):4467-4475)},
  author       = {Agathangelidis, Andreas and Darzentas, Nikos and Hadzidimitriou, Anastasia and Brochet, Xavier and Murray, Fiona and Yan, Xiao-Jie and Davis, Zadie and van Gastel-Mol, Ellen J. and Tresoldi, Cristina and Chu, Charles C. and Cahill, Nicola and Giudicelli, Veronique and Tichy, Boris and Pedersen, Lone Bredo and Foroni, Letizia and Bonello, Lisa and Janus, Agnieszka and Smedby, Karin and Anagnostopoulos, Achilles and Merle-Beral, Helene and Laoutaris, Nikolaos and Juliusson, Gunnar and di Celle, Paola Francia and Pospisilova, Sarka and Jurlander, Jesper and Geisler, Christian and Tsaftaris, Athanasios and Lefranc, Marie-Paule and Langerak, Anton W. and Oscier, David Graham and Chiorazzi, Nicholas and Belessi, Chrysoula and Davi, Frederic and Rosenquist, Richard and Ghia, Paolo and Stamatopoulos, Kostas},
  issn         = {1528-0020},
  language     = {eng},
  number       = {19},
  pages        = {4467--4475},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies},
  url          = {http://dx.doi.org/10.1182/blood-2011-11-393694},
  volume       = {119},
  year         = {2012},
}