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.
Highlights
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
We demonstrate the poor prognosis of IGLV3-21R110–expressing CLL and propose to replace the conventionally defined CLL subset 2 with this “subset 2L.”
We performed immunophenotyping and determined the frequency of the IGLV3-21R110 light chains (LCs) as compared with IGLV3-21 (Fig. 1A and SI Appendix, Fig. S1B) in analysis cohort (AC) I consisting of 154 CLL patients, of which complete informative follow-up data and mutational analyses were available for 122 cases (SI Appendix, Tables S1–S6)
Summary
Monoclonal Antibodies Reveal a High Frequency of IGLV3-21R110. We generated 2 highly specific monoclonal antibodies to characterize wild-type (wt) IGLV3-21 and mutated IGLV3-21R110 LC expression in primary CLL samples (Fig. 1A and SI Appendix, Fig. S1 A and B). Immunophenotyping and sequencing analyses revealed that 23 and 10 CLL cases expressed mutated IGLV3-21R110 (17.16%) and unmutated IGLV3-21 (7.46%), respectively (SI Appendix, Fig. S1D). Allocating the IGLV3-21R110 CLL patients according to their IGHV mutational status and comparing the outcome revealed that M- and UM-CLL subgroup OSs were virtually identical (SI Appendix, Fig. S3C). When restricting the analysis to patients not receiving allo-PBSCT, the outcome of the remaining 6 IGLV321R110 CLL cases was inferior compared with M-CLL in terms of progression-free survival (PFS), possibly inferior with respect to OS, and similar to UM-CLL (Fig. 4B) Taken together, these results from a prospective multicenter trial confirm that IGLV3-21R110 CLL represents a clinically aggressive group even within a select high-risk CLL cohort Three HD clusters, 1 through 3, resemble major peripheral B cell subpopulations, namely mature naïve (CD23++, CD38+, IgM+, IgD+), immature (CD23+, CD38++, IgM++, IgD+), and memory-like (CD23−, CD38−, IgM++, IgD+) B cells, respectively (SI Appendix, Fig. S5D)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have