title: Syk inhibition with fostamatinib leads to transitional B lymphocyte depletion.
abstract: Cell signaling initiated by the B cell receptor is critical to normal development of B lymphocytes, most notably at the transitional B cell stage. Inhibition of this signaling pathway with the syk inhibitor, fostamatinib, has produced significant efficacy in lymphoid malignancies and autoimmune conditions. Here, we demonstrate that short-term use of fostamatinib impairs B lymphocyte development at the transitional stage without affecting mature B cell populations. Additionally, IL-10 producing B cells remained relatively constant throughout the treatment period. These findings provide insight into the mechanism of action of B cell receptor inhibition in autoimmune disease. As the development of agents targeting B cell receptor signaling proceeds, monitoring for long-term consequences as well as functional evaluation of B cell subsets may further improve our understanding of this rapidly growing class of novel agents.
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Barr
authors.forename: Chungwen
authors.initials: C
authors.lastname: Wei
authors.forename: James
authors.initials: J
authors.lastname: Roger
authors.forename: Julia
authors.initials: J
authors.lastname: Schaefer-Cutillo
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Kelly
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Rosenberg
authors.forename: John
authors.initials: J
authors.lastname: Jung
authors.forename: Iñaki
authors.initials: I
authors.lastname: Sanz
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Friedberg
mesh_terms: D000631:Aminopyridines; D002454:Cell Differentiation / Q000187:drug effects*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines; D000072377:Syk Kinase
chemical_list: D000631:Aminopyridines; C508609:IL10 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D016753:Interleukin-10; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C523665:fostamatinib