title: Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling.
abstract: B-cell antigen receptor (BCR) expression is an important feature of chronic lymphocytic leukaemia (CLL), one of the most prevalent B-cell neoplasias in Western countries. The presence of stereotyped and quasi-identical BCRs in different CLL patients suggests that recognition of specific antigens might drive CLL pathogenesis. Here we show that, in contrast to other B-cell neoplasias, CLL-derived BCRs induce antigen-independent cell-autonomous signalling, which is dependent on the heavy-chain complementarity-determining region (HCDR3) and an internal epitope of the BCR. Indeed, transferring the HCDR3 of a CLL-derived BCR provides autonomous signalling capacity to a non-autonomously active BCR, whereas mutations in the internal epitope abolish this capacity. Because BCR expression was required for the binding of secreted CLL-derived BCRs to target cells, and mutations in the internal epitope reduced this binding, our results indicate a new model for CLL pathogenesis, with cell-autonomous antigen-independent signalling as a crucial pathogenic mechanism.
authors.affiliation: Centre for Biological Signaling Studies (BIOSS), Albert-Ludwigs Universität Freiburg, 79104 Freiburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dühren-von Minden
authors.forename: Rudolf
authors.initials: R
authors.lastname: Übelhart
authors.forename: Dunja
authors.initials: D
authors.lastname: Schneider
authors.forename: Thomas
authors.initials: T
authors.lastname: Wossning
authors.forename: Martina P
authors.initials: MP
authors.lastname: Bach
authors.forename: Maike
authors.initials: M
authors.lastname: Buchner
authors.forename: Daniel
authors.initials: D
authors.lastname: Hofmann
authors.forename: Elena
authors.initials: E
authors.lastname: Surova
authors.forename: Marie
authors.initials: M
authors.lastname: Follo
authors.forename: Fabian
authors.initials: F
authors.lastname: Köhler
authors.forename: Hedda
authors.initials: H
authors.lastname: Wardemann
authors.forename: Katja
authors.initials: K
authors.lastname: Zirlik
authors.forename: Hendrik
authors.initials: H
authors.lastname: Veelken
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
mesh_terms: D020816:Amino Acid Motifs; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling; D022801:Complementarity Determining Regions / Q000276:immunology / Q000378:metabolism; D018985:Epitopes, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001324:Autoantigens; D022801:Complementarity Determining Regions; D018985:Epitopes, B-Lymphocyte; D011947:Receptors, Antigen, B-Cell