title: B-cell receptor translocation to lipid rafts and associated signaling differ between prognostically important subgroups of chronic lymphocytic leukemia.
abstract: Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease in which interaction of the malignant cells with antigen is thought to play a key role. Individual CLL-cell clones markedly differ in their ability to respond to B-cell receptor ligation, but the mechanism underlying the frequent hyporesponsiveness is incompletely understood. Our aim was to further clarify the extent and cause of the B-cell receptor signaling abnormality in CLL and to assign pathophysiologic relevance to the presence or absence of B-cell receptor responsiveness. We show that extracellular signal-regulated kinase-2 phosphorylation, intracellular Ca2+ increases, CD79a phosphorylation, and translocation of the B-cell receptor to lipid rafts in response to ligation with anti-immunoglobulin M (as a surrogate for antigen) are features of CLL cells with relatively unmutated VH genes (<5% deviation from germ line) and a poor prognosis. B-cell receptor stimulation in these cases also promoted cell survival. In clones with mutated VH genes (>5% deviation from germ line), surface immunoglobulin M ligation failed to induce receptor translocation to rafts or to prolong cell survival. This failure of receptor translocation observed in mutated CLL cells was associated with the constitutive exclusion of the B-cell receptor from rafts by a mechanism involving src-dependent interactions between the B-cell receptor and the actin cytoskeleton. We conclude that exposure to antigen promotes the survival of unmutated CLL clones, contributing to the poor prognosis of this group. In contrast, hyporesponsive mutated CLL clones may have developed into a stage where continuous exposure to antigen results in relative tolerance to antigenic stimulation mediated by the exclusion of the B-cell receptor from lipid rafts.
authors.affiliation: Department of Haematology, Royal Liverpool University Hospital, Liverpool, United Kingdom. david.allsup@hey.nhs.uk
authors.forename: David J
authors.initials: DJ
authors.lastname: Allsup
authors.forename: Aura S
authors.initials: AS
authors.lastname: Kamiguti
authors.forename: Ke
authors.initials: K
authors.lastname: Lin
authors.forename: Paul D
authors.initials: PD
authors.lastname: Sherrington
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Matrai
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Slupsky
authors.forename: John C
authors.initials: JC
authors.lastname: Cawley
authors.forename: Mirko
authors.initials: M
authors.lastname: Zuzel
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D051925:CD79 Antigens; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D021962:Membrane Microdomains / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009154:Mutation; D009367:Neoplasm Staging; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D051925:CD79 Antigens; C497881:CD79A protein, human; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D019950:Mitogen-Activated Protein Kinase 1; D002118:Calcium