Abstract
Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Animals
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Antineoplastic Agents / pharmacology*
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Cell Adhesion Molecules / biosynthesis
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Cell Adhesion Molecules / genetics
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Cell Survival / drug effects
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Cell Survival / physiology
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Chemokine CCL3 / metabolism
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Chemokine CCL4 / metabolism
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Chemotaxis / drug effects
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Chemotaxis / physiology
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Coculture Techniques
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Drug Screening Assays, Antitumor
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Female
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / physiology
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Leukemia, Lymphocytic, Chronic, B-Cell / enzymology
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
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Lymphocyte Activation / drug effects*
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Male
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Mice
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Middle Aged
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / metabolism
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Neoplasm Proteins / physiology
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Oxazines / pharmacology*
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Protein Kinase Inhibitors / pharmacology*
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Protein Processing, Post-Translational / drug effects
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / physiology
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Pyridines / pharmacology*
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Receptors, Antigen, B-Cell / physiology*
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Receptors, Chemokine / biosynthesis
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Receptors, Chemokine / genetics
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Signal Transduction / drug effects*
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Stromal Cells / physiology
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Syk Kinase
Substances
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Antineoplastic Agents
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CCL3 protein, human
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CCL4 protein, human
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Cell Adhesion Molecules
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Chemokine CCL3
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Chemokine CCL4
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Intracellular Signaling Peptides and Proteins
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N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
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Neoplasm Proteins
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Oxazines
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Protein Kinase Inhibitors
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Pyridines
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Receptors, Antigen, B-Cell
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Receptors, Chemokine
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Syk protein, mouse