title: Altered calcium signal transduction in B-1 malignant cells.
abstract: Lymphocyte proliferation is guided by receptor-mediated signal transduction pathways that dictate the immunological response/clonality of that cell. We have previously reported that NZB-derived malignant B-1 cells, which serve as a murine model for human chronic lymphocytic leukaemia, demonstrate altered expression of surface IgM and CD45 signalling molecules, and a failure to proliferate following membrane IgM stimulation. To examine receptor-mediated cytosolic calcium (Cai) signalling in B cell leukaemia, we studied IgM-induced Cai responses in malignant B-1 cells and B cells from non-leukaemic mice. Basal Cai was slightly lower in malignant B-1 cells than in non-leukaemic cells. Anti-IgM stimulation induced a sustained increase in Cai to levels 1.3-fold greater than basal Cai in conventional B cells. In contrast, leukaemic B-1 cells demonstrated a sharp but transient rise in Cai followed by a gradual increase to levels 2.3-fold greater than basal [Ca]i Ca influx from extracellular sources contributed to the early and late Cai signal in both sets of cells. Pre-incubation (2-30 min) with anti-CD45 had no effect on basal Cai or the anti-IgM Cai signal in B cells, but reduced the Cai transient in malignant B-1 cells. Additional experiments characterized the effects of phosphorylation/dephosphorylation events on the Cai profile following anti-IgM stimulation. Protein tyrosine kinase inhibitors decreased the anti-IgM-induced Cai transient in malignant B-1 cells by 80%, but only moderately affected (40%) of the Cai response in non-leukaemic B cells. Protein tyrosine phosphatase inhibitors and protein kinase C (PKC) activators attenuated the Cai response to the same degree in normal and leukaemic B cells. These results show that Cai signalling differs widely between non-malignant B cells and malignant B-1 cells, and that tyrosine phosphorylation and CD45 modulation of IgM signalling are involved in the altered Cai responses in malignant B-1 cells.
authors.affiliation: Department of Pathology, Newark, NJ 07103, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Dang
authors.forename: M
authors.initials: M
authors.lastname: Balasubramanyam
authors.forename: Z
authors.initials: Z
authors.lastname: Garcia
authors.forename: E
authors.initials: E
authors.lastname: Raveche
authors.forename: J P
authors.initials: JP
authors.lastname: Gardner
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002461:Cell Line, Transformed; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology; D015448:Leukemia, B-Cell / Q000276:immunology / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008814:Mice, Inbred NZB; D011493:Protein Kinase C / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D015220:Calcium Channels; D007075:Immunoglobulin M; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D017493:Leukocyte Common Antigens; D017027:Protein Tyrosine Phosphatases