Expression of Functional Sphingosine-1 Phosphate Receptor-1 Is Reduced by B Cell Receptor Signaling and Increased by Inhibition of PI3 Kinase δ but Not SYK or BTK in Chronic Lymphocytic Leukemia Cells



Till, Kathleen J ORCID: 0000-0002-3172-5771, Pettitt, Andrew and Slupsky, Joseph ORCID: 0000-0002-7410-9004
(2015) Expression of Functional Sphingosine-1 Phosphate Receptor-1 Is Reduced by B Cell Receptor Signaling and Increased by Inhibition of PI3 Kinase δ but Not SYK or BTK in Chronic Lymphocytic Leukemia Cells. Journal of Immunology, 194 (5). pp. 2439-2446.

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Abstract

BCR signaling pathway inhibitors such as ibrutinib, idelalisib, and fostamatinib (respective inhibitors of Bruton's tyrosine kinase, PI3Kδ, and spleen tyrosine kinase) represent a significant therapeutic advance in B cell malignancies, including chronic lymphocytic leukemia (CLL). These drugs are distinctive in increasing blood lymphocytes while simultaneously shrinking enlarged lymph nodes, suggesting anatomical redistribution of CLL cells from lymph nodes into the blood. However, the mechanisms underlying this phenomenon are incompletely understood. In this study, we showed that the egress receptor, sphingosine-1-phosphate (S1P) receptor 1 (S1PR1), was expressed at low levels in normal germinal centers and CLL lymph nodes in vivo but became upregulated on normal B cells and, to a variable and lesser extent, CLL cells following in vitro incubation in S1P-free medium. Spontaneous recovery of S1PR1 expression on normal B and CLL cells was prevented by BCR cross-linking, whereas treatment of CLL cells with idelalisib increased S1PR1 expression and migration toward S1P, the greatest increase occurring in cases with unmutated IgH V region genes. Intriguingly, ibrutinib and fostamatinib had no effect on S1PR1 expression or function. Conversely, chemokine-induced migration, which requires integrin activation and is essential for the entry of lymphocytes into lymph nodes as well as their retention, was blocked by ibrutinib and fostamatinib, but not idelalisib. In summary, our results suggest that different BCR signaling inhibitors redistribute CLL cells from lymph nodes into the blood through distinct mechanisms: idelalisib actively promotes egress by upregulating S1PR1, whereas fostamatinib and ibrutinib may reduce CLL cell entry and retention by suppressing chemokine-induced integrin activation.

Item Type: Article
Uncontrolled Keywords: Germinal Center, Lymph Nodes, B-Lymphocytes, Humans, Sphingosine, Aminopyridines, Oxazines, Morpholines, Piperidines, Pyrazoles, Pyridines, Pyrimidines, Purines, Adenine, Lysophospholipids, Intracellular Signaling Peptides and Proteins, Receptors, Lysosphingolipid, Integrins, Receptors, Antigen, B-Cell, Antineoplastic Agents, Protein Kinase Inhibitors, Case-Control Studies, Signal Transduction, Cell Movement, Gene Expression Regulation, Leukemic, Protein-Tyrosine Kinases, Quinazolinones, Leukemia, Lymphocytic, Chronic, B-Cell, Class I Phosphatidylinositol 3-Kinases, Human Umbilical Vein Endothelial Cells, Primary Cell Culture, Syk Kinase, Agammaglobulinaemia Tyrosine Kinase, Sphingosine-1-Phosphate Receptors
Subjects: ?? RZ ??
Depositing User: Symplectic Admin
Date Deposited: 25 Mar 2015 11:55
Last Modified: 16 Dec 2022 04:43
DOI: 10.4049/jimmunol.1402304
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URI: https://livrepository.liverpool.ac.uk/id/eprint/2006413

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