IGLV3-21 * 01 is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling

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.

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

“…9 (G>C, glycine-arginine) of IGLV3-21*01 mediated by somatic hypermutation confers autonomous BCR signaling. 24 This change is present in 7-18% of CLL and seems responsible for the adverse outcome associated with the use of IGLV3-21 independently of the mutational status of the IGHV. 24,25 Epigenetic studies have shown that, although both CLL subtypes are antigen-experienced, M-CLL keeps a methylation signature of germinal center-experienced cells (memory-like B cells), whereas U-CLL has a pre-germinal center, naïve-like methylation signature .5,26 Of note, these epigenetic studies also identified a third subtype with an intermediate profile made of cases with moderate IGHV mutation levels.…”

Mass Cytometry—A Tool for the Curious: Networking in Berlin

“…GerMaNet also helps the swift distribution of new reagents and data analysis tools among the centers. This approach has proven highly effective, as reflected by several joint publications within the GerMaNet .…”

Reading the B-cell receptor immunome in chronic lymphocytic leukemia: revelations and applications

“…homotypic interaction between the LC and the CDR2 loop of another BCR ( [31]. A recently published article reported that the use of IGLV3-21 with this specific substitution (IGLV3-21 R110 in the authors' nomenclature) facilitates homotypic interaction in allele IGLV3-21*01 only [32]. The prevalence of this specific combination of mutation and allele is not confined to subset 2, but can be detected in up to »20% of CLL cases, despite being virtually absent in the BCR repertoire of healthy donors.…”

“…The prevalence of this specific combination of mutation and allele is not confined to subset 2, but can be detected in up to »20% of CLL cases, despite being virtually absent in the BCR repertoire of healthy donors. Consequently, the authors define a subset "2L" based on the presence of IGLV3-21 R110 , which currently constitutes the largest CLL subset, and report the inferior prognosis of patients belonging to this subset in three independent cohorts [32].…”