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IGLV3-21*01 is an inherited risk factor for CLL throughthe acquisition of a single-point mutation enablingautonomous BCR signaling
- Publication Year :
- 2020
- Publisher :
- Universität Ulm, 2020.
-
Abstract
- 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.<br />publishedVersion
- Subjects :
- GENES
Survival
Überleben
Receptors, Antigen, B-Cell
Immunoglobulins
Prognose
Immunophenotyping
13Q14
DDC 570 / Life sciences
Antigens, CD
ddc:570
chronic lymphocytic leukemia (CLL)
LENGTH
ddc:610
PROGNOSTIC INDEX
immunoglobulin allele IGLV3-21*01
autonomous BCR signaling
Immunogenetic phenomena
Prognosis
B-Lymphozyten-Rezeptor
Leukemia, Lymphocytic, Chronic, B-Cell
DELETIONS
Antigen CD38
CD38 EXPRESSION
IMMUNOGLOBULIN HEAVY
Immunglobuline
Chronisch-lymphatische Leukämie
B cell antigen receptor (BCR)
DDC 610 / Medicine & health
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....ca16bb4d763543797aeca1e4533daf65