title: BCR and chemokine responses upon anti-IgM and anti-IgD stimulation in chronic lymphocytic leukaemia.
abstract: Dysregulation of B cell receptor (BCR) signalling is a hallmark of chronic lymphocytic leukaemia (CLL) pathology, and targeting BCR pathway kinases has brought great therapeutic advances. Activation of the BCR in lymphoid organs has been associated with CLL cell proliferation and survival, leading to progressive disease. While these responses are mediated predominantly by IgM, the role of IgD is less clear. Seeking to uncover downstream consequences of individual and combined stimulation of the two BCR isotypes, we found an amplification of IgD expression and IgD-mediated calcium signalling by previous stimulation of IgM in CLL. Furthermore, no heterologous downmodulation of the isotypes, as observed in healthy donors, was present. Only marginal downregulation of the expression of various chemokine receptors by α-IgM and α-IgD stimulation was found as compared to normal B cells. Consistently, calcium responses of CLL cells to different chemokines were only weakly affected by preceding BCR activation. In contrast, migration towards the two homeostatic chemokines CXCL12 and CCL21 was differentially regulated by IgM and IgD. While IgM activation reduced migration of CLL cells towards CXCL12, but not CCL21, IgD activation predominantly impacted on CCL21 but not CXCL12-mediated chemotaxis. This indicates that the preference for one chemokine over the other may depend on the functional presence of the two isotypes in CLL. Inhibitors against the kinases Syk, Lyn, and Btk antagonised both BCR- and chemokine-induced calcium signals.
authors.affiliation: Freiburg University Medical Center, Department of Hematology and Oncology, Albert-Ludwigs-University Freiburg, Breisgau, Germany.|Laboratory for Immunological and Molecular Cancer Research, Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Haerzschel
authors.affiliation: Freiburg University Medical Center, Department of Hematology and Oncology, Albert-Ludwigs-University Freiburg, Breisgau, Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: Catusse
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hutterer
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Manuela
authors.initials: M
authors.lastname: Paunovic
authors.affiliation: Freiburg University Medical Center, Department of Hematology and Oncology, Albert-Ludwigs-University Freiburg, Breisgau, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Zirlik
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center and University Freiburg, Freiburg, Germany.|Division of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Krenn
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. t.hartmann@salk.at.|Salzburg Cancer Research Institute, Salzburg, Austria. t.hartmann@salk.at.
authors.forename: Tanja N
authors.initials: TN
authors.lastname: Hartmann
authors.affiliation: Freiburg University Medical Center, Department of Hematology and Oncology, Albert-Ludwigs-University Freiburg, Breisgau, Germany.|Faculty Medical and Life Sciences, Campus Villingen-Schwenningen, University Furtwangen, Schwarzwald, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Burger
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D054421:Chemokine CCL21 / Q000819:agonists / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000819:agonists / Q000378:metabolism*; D018925:Chemokines / Q000819:agonists / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D011947:Receptors, Antigen, B-Cell / Q000819:agonists / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000888:Antibodies, Anti-Idiotypic; C515478:CCL21 protein, human; C515255:CXCL12 protein, human; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D018925:Chemokines; D011947:Receptors, Antigen, B-Cell; C039951:anti-IgD; C044203:anti-IgM
keywords: BCR signalling; CLL; Chemokines; IgD; IgM