title: Syk-induced phosphatidylinositol-3-kinase activation in Epstein-Barr virus posttransplant lymphoproliferative disorder.
abstract: Posttransplant lymphoproliferative disorder (PTLD)-associated Epstein-Barr virus (EBV)+ B cell lymphomas are serious complications of solid organ and bone marrow transplantation. The EBV protein LMP2a, a B cell receptor (BCR) mimic, provides survival signals to virally infected cells through Syk tyrosine kinase. Therefore, we explored whether Syk inhibition is a viable therapeutic strategy for EBV-associated PTLD. We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol-3'-kinase (PI3K)/Akt signaling in EBV+ B cell lymphoma PTLD lines in vitro. However, Syk inhibition did not inhibit or delay the in vivo growth of solid tumors established from EBV-infected B cell lines. Instead, we observed tumor growth in adjacent inguinal lymph nodes exclusively in fostamatinib-treated animals. In contrast, direct inhibition of PI3K/Akt significantly reduced tumor burden in a xenogeneic mouse model of PTLD without evidence of tumor growth in adjacent inguinal lymph nodes. Taken together, our data indicate that Syk activates PI3K/Akt signaling which is required for survival of EBV+ B cell lymphomas. PI3K/Akt signaling may be a promising therapeutic target for PTLD, and other EBV-associated malignancies.
authors: Program in Immunology, Stanford University School of Medicine, Stanford, CA.|Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.
authors: O
authors: O
authors: Hatton
authors: Program in Immunology, Stanford University School of Medicine, Stanford, CA.|Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.
authors: S L
authors: SL
authors: Lambert
authors: Program in Immunology, Stanford University School of Medicine, Stanford, CA.|Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.
authors: L K
authors: LK
authors: Phillips
authors: Program in Immunology, Stanford University School of Medicine, Stanford, CA.|Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.
authors: M
authors: M
authors: Vaysberg
authors: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors: Y
authors: Y
authors: Natkunam
authors: Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.
authors: C O
authors: CO
authors: Esquivel
authors: Program in Immunology, Stanford University School of Medicine, Stanford, CA.|Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.
authors: S M
authors: SM
authors: Krams
authors: Program in Immunology, Stanford University School of Medicine, Stanford, CA.|Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.
authors: O M
authors: OM
authors: Martinez
mesh_terms: D000631:Aminopyridines; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D020031:Epstein-Barr Virus Infections / Q000201:enzymology*; D004854:Herpesvirus 4, Human; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008198:Lymph Nodes / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000201:enzymology* / Q000821:virology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011183:Postoperative Complications; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines; D015398:Signal Transduction; D000072377:Syk Kinase; D014183:Transplantation, Heterologous
chemical_list: D000631:Aminopyridines; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; D000072377:Syk Kinase; C000606896:SYK protein, human; C000606897:Syk protein, mouse; C523665:fostamatinib
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