IGLV3-21∗01 is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling: Proceedings of the National Academy of Sciences of the United States of America

P.C. Maity, M. Bilal, M.T. Koning, M. Young, C.A.M. Van Bergen, V. Renna, A. Nicolò, M. Datta, E. Gentner-Göbel, R.S. Barendse, S.F. Somers, R.A.L. De Groen, J.S.P. Vermaat, D. Steinbrecher, C. Schneider, E. Tausch, T. Bittolo, R. Bomben, A.N. Mazzarello, G. Del PoetaW.G.M. Kroes, J.T. Van Wezel, K. Imkeller, C.E. Busse, M. Degano, T. Bakchoul, A.R. Schulz, H. Mei, P. Ghia, K. Kotta, K. Stamatopoulos, H. Wardemann, A. Zucchetto, N. Chiorazzi, V. Gattei, S. Stilgenbauer, H. Veelken, H. Jumaa

Research output: Contribution to journalArticlepeer-review


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 complementaritydetermining 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 ofmonoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21R110 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors. © 2020 National Academy of Sciences. All rights reserved.
Original languageEnglish
Pages (from-to)4320-4327
Number of pages8
JournalProc. Natl. Acad. Sci. U. S. A.
Issue number8
Publication statusPublished - 2020


  • 01
  • Autonomous BCR signaling
  • B cell antigen receptor (BCR)
  • Chronic lymphocytic leukemia (CLL)
  • Immunoglobulin allele IGLV3-21
  • B cell antigen receptor
  • lymphocyte antigen receptor
  • monoclonal antibody
  • unclassified drug
  • immunoglobulin heavy chain
  • immunoglobulin lambda chain
  • allele
  • Article
  • cancer prognosis
  • chronic lymphatic leukemia
  • controlled study
  • follow up
  • gene
  • gene expression
  • gene mutation
  • genetic association
  • heavy chain
  • human
  • human cell
  • IGLV3 21 01 gene
  • immunophenotyping
  • light chain
  • major clinical study
  • phenotype
  • priority journal
  • risk factor
  • signal transduction
  • single point mutation
  • wild type
  • B lymphocyte
  • cohort analysis
  • complementarity determining region
  • genetic predisposition
  • genetics
  • immunology
  • point mutation
  • B-Lymphocytes
  • Cohort Studies
  • Complementarity Determining Regions
  • Genetic Predisposition to Disease
  • Humans
  • Immunoglobulin Heavy Chains
  • Immunoglobulin lambda-Chains
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Point Mutation
  • Receptors, Antigen, B-Cell


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