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.
Highlights
B cell receptor (BCR) signaling plays a critical role in driving proliferation and survival of the malignant clone inThese authors contributed : Mascha Binder, Peter Nollau
From the nine characterized Signaling Lymphocytic Activation Molecule Family (SLAMF) receptors, we chose SLAMF1 and SLAMF7 that are expressed in Chronic Lymphocytic Leukemia (CLL), but on average downregulated in comparison to normal B cells and that carry a cytoplasmic phosphorylation site able to bind to downstream signaling adapters [12]
Research from the last two decades showing that the BCR is a major driver in CLL has profoundly transformed our therapeutic landscape with the introduction of BCR pathway antagonists in essentially all treatment lines
Summary
B cell receptor (BCR) signaling plays a critical role in driving proliferation and survival of the malignant clone in. In the work presented here, we provide compelling data that SLAMF1 and SLAMF7 receptors may enhance immune control of CLL and negatively regulate BCR signaling and thereby impact sensitivity towards BTK inhibition in the substantial fraction of patients with SLAMF1 or SLAMF7 expressing M-CLL.
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