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Functional Differences between IgM and IgD Signaling in Chronic Lymphocytic Leukemia.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2016 Sep 15; Vol. 197 (6), pp. 2522-31. Date of Electronic Publication: 2016 Aug 17. - Publication Year :
- 2016
-
Abstract
- BCR signaling is a central pathogenetic pathway in chronic lymphocytic leukemia (CLL). Most CLL cells express BCRs of IgM and IgD isotypes, but the contribution of these isotypes to functional responses remains incompletely defined. We therefore investigated differences between IgM and IgD signaling in freshly isolated peripheral blood CLL cells and in CLL cells cultured with nurselike cells, a model that mimics the lymph node microenvironment. IgM signaling induced prolonged activation of ERK kinases and promoted CLL cell survival, CCL3 and CCL4 chemokine secretion, and downregulation of BCL6, the transcriptional repressor of CCL3 In contrast, IgD signaling induced activation of the cytoskeletal protein HS1, along with F-actin polymerization, which resulted in rapid receptor internalization and failure to support downstream responses, including CLL cell survival and chemokine secretion. IgM and IgD receptor downmodulation, HS1 and ERK activation, chemokine secretion, and BCL6 downregulation were also observed when CLL cells were cocultured with nurselike cells. The Bruton's tyrosine kinase inhibitor ibrutinib effectively inhibited both IgM and IgD isotype signaling. In conclusion, through a variety of functional readouts, we demonstrate very distinct outcomes of IgM and IgD isotype activation in CLL cells, providing novel insight into the regulation of BCR signaling in CLL.<br /> (Copyright © 2016 by The American Association of Immunologists, Inc.)
- Subjects :
- Adaptor Proteins, Signal Transducing
B-Lymphocytes metabolism
Blood Proteins genetics
Blood Proteins metabolism
Cell Survival immunology
Cells, Cultured
Cellular Microenvironment immunology
Chemokine CCL3 immunology
Chemokine CCL3 metabolism
Chemokine CCL4 immunology
Chemokine CCL4 metabolism
Gene Expression Regulation
Humans
Immunoglobulin D immunology
Immunoglobulin M immunology
Intracellular Signaling Peptides and Proteins metabolism
Leukemia, Lymphocytic, Chronic, B-Cell physiopathology
Lymph Nodes cytology
Lymph Nodes immunology
Protein-Tyrosine Kinases immunology
Proto-Oncogene Proteins c-bcl-6 genetics
Receptors, Antigen, B-Cell genetics
Receptors, Antigen, B-Cell immunology
Immunoglobulin D metabolism
Immunoglobulin M metabolism
Leukemia, Lymphocytic, Chronic, B-Cell immunology
Receptors, Antigen, B-Cell metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 197
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 27534555
- Full Text :
- https://doi.org/10.4049/jimmunol.1600915