title: 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.
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.
authors: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3GA, United Kingdom k.j.till@liv.ac.uk.
authors: Kathleen J
authors: KJ
authors: Till
authors: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3GA, United Kingdom.
authors: Andrew R
authors: AR
authors: Pettitt
authors: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3GA, United Kingdom.
authors: Joseph R
authors: JR
authors: Slupsky
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000631:Aminopyridines; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D002465:Cell Movement; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000276:immunology; D015973:Gene Expression Regulation, Leukemic; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008246:Lysophospholipids / Q000276:immunology / Q000378:metabolism; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology; D010880:Piperidines; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D049349:Receptors, Lysosphingolipid / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D000072377:Syk Kinase
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D009025:Morpholines; D010078:Oxazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D052999:Quinazolinones; D011947:Receptors, Antigen, B-Cell; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C551803:ibrutinib; C060506:sphingosine 1-phosphate; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000606896:SYK protein, human; D000072377:Syk Kinase; D000225:Adenine; D013110:Sphingosine; C523665:fostamatinib; C552946:idelalisib
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