Syk-Induced Phosphatidylinositol-3-Kinase Activation in Epstein–Barr Virus Posttransplant Lymphoproliferative Disorder

Authors

  • O. Hatton,

    1. Program in Immunology, Stanford University School of Medicine, Stanford, CA
    2. Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA
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  • S. L. Lambert,

    1. Program in Immunology, Stanford University School of Medicine, Stanford, CA
    2. Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA
    Current affiliation:
    1. MedImmune, CA
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  • L. K. Phillips,

    1. Program in Immunology, Stanford University School of Medicine, Stanford, CA
    2. Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA
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  • M. Vaysberg,

    1. Program in Immunology, Stanford University School of Medicine, Stanford, CA
    2. Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA
    Current affiliation:
    1. Gilead, Foster City, CA
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  • Y. Natkunam,

    1. Department of Pathology, Stanford University School of Medicine, Stanford, CA
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  • C. O. Esquivel,

    1. Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA
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  • S. M. Krams,

    1. Program in Immunology, Stanford University School of Medicine, Stanford, CA
    2. Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA
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  • O. M. Martinez

    Corresponding author
    1. Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA
    • Program in Immunology, Stanford University School of Medicine, Stanford, CA
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Olivia M. Martinez,

omm@stanford.edu

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.

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