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Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4320-4327. doi: 10.1073/pnas.1913810117. Epub 2020 Feb 11.

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

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Institute of Immunology, Ulm University, 89081 Ulm, Germany.
Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Department of Internal Medicine III, Ulm University Hospital, 89081 Ulm, Germany.
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 33081 Aviano, Italy.
Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030.
Division of Hematology, S. Eugenio Hospital and University of Tor Vergata, 00144 Rome, Italy.
Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
B Cell Immunology, German Cancer Research Center, 69120 Heidelberg, Germany.
Biocrystallography Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Transfusion Medicine, Medical Faculty of Tübingen and Center for Clinical Transfusion Medicine, Universitätsklinikum Tübingen, 72076 Tübingen, Germany.
Mass Cytometry Lab, German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany.
Division of Experimental Oncology, Università Vita-Salute San Raffaele, 20132 Milan, Italy.
Institute of Applied Biosciences, Centre for Research and Technology Hellas, 57001 Thessaloniki, Greece.
Department of Hematology, Oncology, Clinical Immunology, and Rheumatology, Saarland University Medical School, 66421 Homburg/Saar, Germany.
José Carreras Institute for Immunology and Gene Therapy, Saarland University Medical School, 66421 Homburg/Saar, Germany.
Institute of Immunology, Ulm University, 89081 Ulm, Germany;


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.


B cell antigen receptor (BCR); autonomous BCR signaling; chronic lymphocytic leukemia (CLL); immunoglobulin allele IGLV3-21*01

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Conflict of interest statement

Competing interest statement: H.J. is a cofounder of AVA LifeScience GmbH that has filed patents on antibodies recognizing structures involved in autonomous BCR signaling.

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