1. SLAMF receptors negatively regulate B cell receptor signaling in chronic lymphocytic leukemia via recruitment of prohibitin-2
- Author
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Helwe Gerull, Simon Schliffke, Sarah Naomi Bolz, Boris Fehse, Donjete Simnica, Peter Nollau, Christoph Schultheiß, Lisa von Wenserski, Mascha Binder, Gerrit Wolters-Eisfeld, Kristoffer Riecken, Edith Willscher, and Marcus Altfeld
- Subjects
Male ,Cancer Research ,Chronic lymphocytic leukemia ,B-cell receptor ,Cell ,Receptors, Antigen, B-Cell ,Biology ,Models, Biological ,Article ,Gene Knockout Techniques ,Signaling Lymphocytic Activation Molecule Family ,Cell Line, Tumor ,hemic and lymphatic diseases ,Prohibitins ,Biomarkers, Tumor ,medicine ,Humans ,RNA, Small Interfering ,Receptor ,Aged ,Cancer ,Aged, 80 and over ,B-Lymphocytes ,Gene Expression Regulation, Leukemic ,breakpoint cluster region ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Killer Cells, Natural ,Repressor Proteins ,Leukemia ,medicine.anatomical_structure ,Oncology ,Cancer research ,Female ,Disease Susceptibility ,Signal transduction ,Immunoglobulin Heavy Chains ,IGHV@ ,Signal Transduction ,Cell signalling - Abstract
We identified a subset of Chronic Lymphocytic Leukemia (CLL) patients with high Signaling Lymphocytic Activation Molecule Family (SLAMF) receptor-related signaling that showed an indolent clinical course. Since SLAMF receptors play a role in NK cell biology, we reasoned that these receptors may impact NK cell-mediated CLL immunity. Indeed, our experiments showed significantly decreased degranulation capacity of primary NK cells from CLL patients expressing low levels of SLAMF1 and SLAMF7. Since the SLAMFlow signature was strongly associated with an unmutated CLL immunoglobulin heavy chain (IGHV) status in large datasets, we investigated the impact of SLAMF1 and SLAMF7 on the B cell receptor (BCR) signaling axis. Overexpression of SLAMF1 or SLAMF7 in IGHV mutated CLL cell models resulted in reduced proliferation and impaired responses to BCR ligation, whereas the knockout of both receptors showed opposing effects and increased sensitivity toward inhibition of components of the BCR pathway. Detailed molecular analyzes showed that SLAMF1 and SLAMF7 receptors mediate their BCR pathway antagonistic effects via recruitment of prohibitin-2 (PHB2) thereby impairing its role in signal transduction downstream the IGHV-mutant IgM-BCR. Together, our data indicate that SLAMF receptors are important modulators of the BCR signaling axis and may improve immune control in CLL by interference with NK cells.
- Published
- 2020