title: The meaning and relevance of B-cell receptor structure and function in chronic lymphocytic leukemia.
abstract: The B-cell receptor (BCR) is of critical importance for normal B cells and for the majority of B-cell malignancies, especially chronic lymphocytic leukemia (CLL). The two major subsets of CLL are biologically distinct, being derived from B cells at different stages of differentiation and carrying unmutated (U-CLL) or mutated (M-CLL) IGHV genes. U-CLL, which has a poorer prognosis, often has relatively conserved (stereotypic) IGHV-HD-HJ sequences, indicative of interaction with large (super)antigens and similar to those in normal naive innate B cells. Conserved sequences are less evident in M-CLL, in keeping with its postfollicular origin. However, both subsets exhibit features of chronic antigen exposure in tissue sites, with local proliferative events, but also downregulation of surface immunoglobulin M but not surface immunoglobulin D, a characteristic of normal anergic B cells. BCR-mediated anergy can spread to other receptors such as CXCR4. Circulating CLL cells retain a shadow of tissue-based events that can reverse over time, but the overall extent of anergy is greater in M-CLL. Despite this stereotypic variety and more genomic complexity, BCR-mediated responses in vitro appear relatively homogeneous in U-CLL, but M-CLL is more heterogeneous. The differential balance between antigen-induced proliferation or anergy is the likely determinant of clinical behavior and possibly of response to kinase inhibitors.
authors.affiliation: Cancer Sciences Unit, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton, Hampshire, United Kingdom. Electronic address: fs@soton.ac.uk.
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.affiliation: Cancer Sciences Unit, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton, Hampshire, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.affiliation: Cancer Sciences Unit, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton, Hampshire, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C527276:CXCR4 protein, human; D011947:Receptors, Antigen, B-Cell; D019718:Receptors, CXCR4