IGLV3-21*01 is an inherited risk factor for CLL throughthe acquisition of a single-point mutation enablingautonomous BCR signaling
| Autor: | Maity, Palash C., Bilal, Mayas, Koning, Marvyn T., Young, Marc, Van Bergen, Cornelis A. M., Renna, Valerio, Nicolo, Antonella, Datta, Moumita, Gentner-Göbel, Eva, Barendse, Rob S., Somers, Sebastiaan F., De Groen, Ruben A. L., Vermaat, Joost S. P., Steinbrecher, Daniela, Schneider, Christof, Tausch, Eugen, Bittolo, Tamara, Bomben, Riccardo, Mazzarello, Andrea Nicola, Del Poeta, Giovanni, Kroes, Wilma G. M., Van Wezel, J. Tom, Imkeller, Katharina, Busse, Christian E., Degano, Massimo, Bakchoul, Tamam, Schulz, Axel Ronald, Mei, Henrik, Ghia, Paolo, Kotta, Konstantia, Stamatopoulos, Kostas, Wardemann, Hedda, Zucchetto, Antonella, Chiorazzi, Nicholas, Gattei, Valter, Stilgenbauer, Stephan, Veelken, Hendrik, Jumaa, Hassan |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
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 |
| Popis: | 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. publishedVersion |
| Databáze: | OpenAIRE |
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