TY - JOUR

T1 - Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia

T2 - a molecular classification with implications for targeted therapies

AU - Agathangelidis, Andreas

AU - Darzentas, Nikos

AU - Hadzidimitriou, Anastasia

AU - Brochet, Xavier

AU - Murray, Fiona

AU - Yan, Xiao-Jie

AU - Davis, Zadie

AU - van Gastel-Mol, Ellen J

AU - Tresoldi, Cristina

AU - Chu, Charles C

AU - Cahill, Nicola

AU - Giudicelli, Veronique

AU - Tichy, Boris

AU - Pedersen, Lone Bredo

AU - Foroni, Letizia

AU - Bonello, Lisa

AU - Janus, Agnieszka

AU - Smedby, Karin

AU - Anagnostopoulos, Achilles

AU - Merle-Beral, Helene

AU - Laoutaris, Nikolaos

AU - Juliusson, Gunnar

AU - di Celle, Paola Francia

AU - Pospisilova, Sarka

AU - Jurlander, Jesper

AU - Geisler, Christian

AU - Tsaftaris, Athanasios

AU - Lefranc, Marie-Paule

AU - Langerak, Anton W

AU - Oscier, David Graham

AU - Chiorazzi, Nicholas

AU - Belessi, Chrysoula

AU - Davi, Frederic

AU - Rosenquist, Richard

AU - Ghia, Paolo

AU - Stamatopoulos, Kostas

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1182/blood-2011-11-393694

DO - 10.1182/blood-2011-11-393694

M3 - Journal article

C2 - 22415752

VL - 119

SP - 4467

EP - 4475

JO - Blood

JF - Blood

SN - 0006-4971

IS - 19

ER -