title: Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies.
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.
authors.affiliation: Institute of Agrobiotechnology, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Agathangelidis
authors.forename: Nikos
authors.initials: N
authors.lastname: Darzentas
authors.forename: Anastasia
authors.initials: A
authors.lastname: Hadzidimitriou
authors.forename: Xavier
authors.initials: X
authors.lastname: Brochet
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.forename: Zadie
authors.initials: Z
authors.lastname: Davis
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: van Gastel-Mol
authors.forename: Cristina
authors.initials: C
authors.lastname: Tresoldi
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chu
authors.forename: Nicola
authors.initials: N
authors.lastname: Cahill
authors.forename: Veronique
authors.initials: V
authors.lastname: Giudicelli
authors.forename: Boris
authors.initials: B
authors.lastname: Tichy
authors.forename: Lone Bredo
authors.initials: LB
authors.lastname: Pedersen
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
authors.forename: Lisa
authors.initials: L
authors.lastname: Bonello
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Janus
authors.forename: Karin
authors.initials: K
authors.lastname: Smedby
authors.forename: Achilles
authors.initials: A
authors.lastname: Anagnostopoulos
authors.forename: Helene
authors.initials: H
authors.lastname: Merle-Beral
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Laoutaris
authors.forename: Gunnar
authors.initials: G
authors.lastname: Juliusson
authors.forename: Paola Francia
authors.initials: PF
authors.lastname: di Celle
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
authors.forename: Jesper
authors.initials: J
authors.lastname: Jurlander
authors.forename: Christian
authors.initials: C
authors.lastname: Geisler
authors.forename: Athanasios
authors.initials: A
authors.lastname: Tsaftaris
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Lefranc
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
authors.forename: David Graham
authors.initials: DG
authors.lastname: Oscier
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Belessi
authors.forename: Frederic
authors.initials: F
authors.lastname: Davi
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
mesh_terms: D000595:Amino Acid Sequence; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification* / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell