IGLV3-21*01 is an inherited risk factor for CLL throughthe acquisition of a single-point mutation enablingautonomous BCR signaling
Creators: name: Maity, Palash C.
name: Bilal, Mayas
name: Koning, Marvyn T.
name: Young, Marc
name: Van Bergen, Cornelis A. M.
name: Renna, Valerio
name: Nicolo, Antonella
name: Datta, Moumita
name: Gentner-Göbel, Eva
name: Barendse, Rob S.
name: Somers, Sebastiaan F.
name: De Groen, Ruben A. L.
name: Vermaat, Joost S. P.
name: Steinbrecher, Daniela
name: Schneider, Christof
name: Tausch, Eugen
name: Bittolo, Tamara
name: Bomben, Riccardo
name: Mazzarello, Andrea Nicola
name: Del Poeta, Giovanni
name: Kroes, Wilma G. M.
name: Van Wezel, J. Tom
name: Imkeller, Katharina
name: Busse, Christian E.
name: Degano, Massimo
name: Bakchoul, Tamam
name: Schulz, Axel Ronald
name: Mei, Henrik
name: Ghia, Paolo
name: Kotta, Konstantia
name: Stamatopoulos, Kostas
name: Wardemann, Hedda
name: Zucchetto, Antonella
name: Chiorazzi, Nicholas
name: Gattei, Valter
name: Stilgenbauer, Stephan
name: Veelken, Hendrik
name: Jumaa, Hassan
Publisher: name: Universität Ulm
Year: 2020
Subjects: subject: chronic lymphocytic leukemia (CLL)
subject: B cell antigen receptor (BCR)
subject: autonomous BCR signaling
subject: immunoglobulin allele IGLV3-21*01
subject: CD38 EXPRESSION
subject: IMMUNOGLOBULIN HEAVY
subject: PROGNOSTIC INDEX
subject: GENES
subject: DELETIONS
subject: LENGTH
subject: 13Q14
subject: DDC 570 / Life sciences
subject: DDC 610 / Medicine &amp; health
subject: Leukemia, Lymphocytic, Chronic, B-Cell
subject: Receptors, Antigen, B-Cell
subject: Immunoglobulins
subject: Immunophenotyping
subject: Antigens, CD
subject: Immunogenetic phenomena
subject: Survival
subject: Prognosis
subject: Chronisch-lymphatische Leukämie
subject: B-Lymphozyten-Rezeptor
subject: Antigen CD38
subject: Immunglobuline
subject: Überleben
subject: Prognose

description: The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementarity-determining regions (CDRs) classify ∼30% of CLL cases into prognostically important subsets. Subset 2 expresses a BCR with the combination of IGHV3-21–derived heavy chains (HCs) with IGLV3-21–derived light chains (LCs), and is associated with an unfavorable prognosis. Importantly, the subset 2 LC carries a single-point mutation, termed R110, at the junction between the variable and constant LC regions. By analyzing 4 independent clinical cohorts through BCR sequencing and by immunophenotyping with antibodies specifically recognizing wild-type IGLV3-21 and R110-mutated IGLV3-21 (IGLV3-21R110), we show that IGLV3-21R110–expressing CLL represents a distinct subset with poor prognosis independent of IGHV mutations. Compared with other alleles, only IGLV3-21*01 facilitates effective homotypic BCR–BCR interaction that results in autonomous, oncogenic BCR signaling after acquiring R110 as a single-point mutation. Presumably, this mutation acts as a standalone driver that transforms IGLV3-21*01–expressing B cells to develop CLL. Thus, we propose to expand the conventional definition of CLL subset 2 to subset 2L by including all IGLV3-21R110–expressing CLL cases regardless of IGHV mutational status. Moreover, the generation of monoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21R110 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors.