title: Basal Ca(2+) signaling is particularly increased in mutated chronic lymphocytic leukemia.
abstract: On the basis of somatic hypermutation status of their B-cell antigen receptor (BCR) genes, chronic lymphocytic leukemia (CLL) patients can be divided into unmutated CLL (U-CLL) or mutated CLL (M-CLL). Approximately 30% of CLL patients express a stereotypic BCR, which may indicate that specific antigenic stimulation is driving CLL pathogenesis. Recently, it was reported that BCRs from CLL cells are capable of antigen-independent, cell-autonomous signaling, through recognition of an internal framework 2 (FR2) BCR epitope. We hypothesized that the level of cell-autonomous signaling may differ between CLL subgroups. Therefore, we analyzed Ca(2+) signaling in a series of primary stereotypic or heterogeneous U-CLL and M-CLL (n=68) and healthy controls (n=14). We confirmed that basal Ca(2+) signaling in CLL cells is higher than in normal B cells. Interestingly, we found that basal signaling was particularly increased in M-CLL. The degree of basal signaling did not correlate with membrane immunoglobulin levels, HCDR3 characteristics or FR2/FR3 sequence. We conclude that the level of basal Ca(2+) signaling is not uniformly enhanced in CLL B cells, but is associated with CLL immunoglobulin heavy chain V mutational status, reflecting a distinct cellular origin and possibly a different anergic state induced by repetitive or continuous antigen binding in vivo.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: A F
authors.initials: AF
authors.lastname: Muggen
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: S Y
authors.initials: SY
authors.lastname: Pillai
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: L P
authors.initials: LP
authors.lastname: Kil
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: M C
authors.identifier: 0000000341611919
authors.initials: MC
authors.lastname: van Zelm
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: J J M
authors.initials: JJ
authors.lastname: van Dongen
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: R W
authors.initials: RW
authors.lastname: Hendriks
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: A W
authors.initials: AW
authors.lastname: Langerak
mesh_terms: D020816:Amino Acid Motifs; D001402:B-Lymphocytes / Q000166:cytology; D020013:Calcium Signaling; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007136:Immunoglobulins / Q000737:chemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008875:Middle Aged; D009154:Mutation; D010802:Phylogeny
chemical_list: D000939:Epitopes; D007074:Immunoglobulin G; D007136:Immunoglobulins