title: B-cell receptor signaling in chronic lymphocytic leukemia.
abstract: The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies. Recombinatorial and mutational patterns in the clonal immunoglobulin (Ig) of chronic lymphocytic leukemia (CLL) have revealed 2 major IgMD-expressing subsets and an isotype-switched variant, each developing from distinct B-cell populations. Tracking of conserved stereotypic features of Ig variable regions characteristic of U-CLL indicate circulating naive B cells as the likely cells of origin. In CLL, engagement of the BCR by antigen occurs in vivo, leading to down-regulated expression and to an unanticipated modulation of glycosylation of surface IgM, visible in blood cells, especially in U-CLL. Modulated glycoforms of sIgM are signal competent and could bind to environmental lectins. U-CLL cases express more sIgM and have increased signal competence, linking differential signaling responses to clinical behavior. Mapping of BCR signaling pathways identifies targets for blockade, aimed to deprive CLL cells of survival and proliferative signals. New inhibitors of BCR signaling appear to have clinical activity. In this Perspective, we discuss the functional significance of the BCR in CLL, and we describe strategies to target BCR signaling as an emerging therapeutic approach.
authors.affiliation: Molecular Immunology Group, Cancer Sciences, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom. fs@soton.ac.uk
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.forename: Sergey
authors.initials: S
authors.lastname: Krysov
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Davies
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Steele
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007155:Immunologic Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007155:Immunologic Factors; D011947:Receptors, Antigen, B-Cell