title: Stimulation of surface IgM of chronic lymphocytic leukemia cells induces an unfolded protein response dependent on BTK and SYK.
abstract: B-cell receptor (BCR) signaling plays a key role in the behavior of chronic lymphocytic leukemia (CLL). However, cellular consequences of signaling are incompletely defined. Here we explored possible links between BCR signaling and the unfolded protein response (UPR), a stress response pathway that can promote survival of normal and malignant cells. Compared with normal B cells, circulating CLL cells expressed increased, but variable, levels of UPR components. Higher expression of CHOP and XBP1 RNAs was associated with more aggressive disease. UPR activation appeared due to prior tissue-based antigenic stimulation because elevated expression of UPR components was detected within lymph node proliferation centers. Basal UPR activation also correlated closely with surface immunoglobulin M (sIgM) signaling capacity in vitro in both IGHV unmutated CLL and within mutated CLL. sIgM signaling increased UPR activation in vitro with responders showing increased expression of CHOP and XBP1 RNAs, and PERK and BIP proteins, but not XBP1 splicing. Inhibitors of BCR-associated kinases effectively prevented sIgM-induced UPR activation. Overall, this study demonstrates that sIgM signaling results in activation of some components the UPR in CLL cells. Modulation of the UPR may contribute to variable clinical behavior, and its inhibition may contribute to clinical responses to BCR-associated kinase inhibitors.
authors.affiliation: Cancer Research United Kingdom Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom;
authors.forename: Sergey
authors.initials: S
authors.lastname: Krysov
authors.affiliation: Cancer Research United Kingdom Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Steele
authors.affiliation: Cancer Research United Kingdom Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom;
authors.forename: Vania
authors.initials: V
authors.lastname: Coelho
authors.affiliation: Cancer Research United Kingdom Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom;
authors.forename: Adam
authors.initials: A
authors.lastname: Linley
authors.affiliation: Cancer Research United Kingdom Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom;
authors.forename: Marina
authors.initials: M
authors.lastname: Sanchez Hidalgo
authors.affiliation: Cancer Research United Kingdom Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom;
authors.forename: Matthew
authors.initials: M
authors.lastname: Carter
authors.affiliation: Cancer Research United Kingdom Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom;
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Potter
authors.affiliation: Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kennedy
authors.affiliation: Department of Haematology, Southampton General Hospital, Southampton, United Kingdom; and.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Duncombe
authors.affiliation: Cancer Research United Kingdom Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom; Department of Cellular Pathology, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Margaret
authors.initials: M
authors.lastname: Ashton-Key
authors.affiliation: Cancer Research United Kingdom Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom; Department of Haematology, Southampton General Hospital, Southampton, United Kingdom; and.
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.affiliation: Cancer Research United Kingdom Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom;
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.affiliation: Cancer Research United Kingdom Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom;
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction; D000072377:Syk Kinase; D056811:Unfolded Protein Response
chemical_list: D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000606896:SYK protein, human; D000072377:Syk Kinase