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

• DOI: 10.1073/pnas.1913810117
• Publication Date: 2020-02-11T21:55:37Z
• Authors: Palash C. Maity; Mayas Bilal; Marvyn T. Koning; Marc Young; Cornelis A. M. va...; Valerio Renna; Antonella Nicolò; Moumita Datta; Eva Gentner-Göbel; Rob S. Barendse; Sebastiaan F. Somers; Ruben A. L. de Groen; Joost S. P. Vermaat; Daniela Steinbrecher; Christof Schneider; Eugen Tausch; Tamara Bittolo; Riccardo Bomben; Andrea Nicola Maz...; Giovanni del Poeta; Wilma G. M. Kroes; J. Tom van Wezel; Katharina Imkeller; Christian E. Busse; Massimo Degano; Tamam Bakchoul; Axel Ronald Schulz; Henrik Mei; Paolo Ghia; Konstantia Kotta; Kostas Stamatopoulos; Hedda Wardemann; Antonella Zucchetto; Nicholas Chiorazzi; Valter Gattei; Stephan Stilgenbauer; Hendrik Veelken; Hassan Jumaa
• Keywords: 0301 basic medicine; GENES; Survival; Überleben; Immunoglobulin allele IGLV3-21; Immunoglobulins; Prognose; Receptors, Antigen, B-Cell; Immunophenotyping; 01; 13Q14; Cohort Studies; 03 medical and health sciences; Immunoglobulin lambda-Chains; Antigens, CD; chronic lymphocytic leukemia (CLL); Autonomous BCR signaling; LENGTH; Humans; Point Mutation; Genetic Predisposition to Disease; PROGNOSTIC INDEX; info:eu-repo/classification/ddc/610; info:eu-repo/classification/ddc/570; B-Lymphocytes; B cell antigen receptor (BCR); autonomous BCR signaling; chronic lymphocytic leukemia (CLL); immunoglobulin allele IGLV3-21*01; 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; immunoglobulin allele IGLV3-21*01; autonomous BCR signaling; Immunogenetic phenomena; Biological Sciences; Prognosis; B-Lymphozyten-Rezeptor; Complementarity Determining Regions; Leukemia, Lymphocytic, Chronic, B-Cell; Chronic lymphocytic leukemia (CLL); 3. Good health; B cell antigen receptor (BCR); autonomous BCR signaling; chronic lymphocytic leukemia (CLL); immunoglobulin allele IGLV3-21*01; DELETIONS; Antigen CD38; Settore MED/15 - MALATTIE DEL SANGUE; CD38 EXPRESSION; IMMUNOGLOBULIN HEAVY; Immunglobuline; Chronisch-lymphatische Leukämie; B cell antigen receptor (BCR); Immunoglobulin Heavy Chains

Significance

CLL is characterized by autonomous B cell receptor (BCR) signaling. CLL subsets are empirically defined by sequence similarities of the BCR heavy chain. However, in the unfavorable subset 2, an acquired mutation (termed R110) in the light chain stimulates autonomous BCR signaling. This study demonstrates that the oncogenic R110 mutation dictates the unfavorable prognosis and is not restricted to the conventional subset 2. Interestingly, carriers of a particular light-chain allele (

IGLV3-21 * 01

) are predisposed to develop CLL because this allele enables autonomous BCR signaling by R110 as a single-point mutation. Monoclonal antibodies permit convenient screening for R110-expressing CLL, showing that it is the largest immunologically defined CLL subset and an example of functional rather than empirical CLL subclassification.