Abstract
B cell lymphoma survival requires tonic or ligand-independent signals through activation of Syk by the B cell receptor. The Epstein-Barr virus (EBV) protein latent membrane 2a (LMP2a), a mimic of the B cell receptor, provides constitutive survival signals for latently infected cells through Syk activation; however, the precise downstream mechanisms coordinating this survival response in EBV+ B cell lymphomas remain to be elucidated. Herein, we assess the mechanism of Syk survival signaling in EBV+ B cell lymphomas from post-transplant lymphoproliferative disorder (PTLD) to discover virally controlled therapeutic targets involved in lymphomagenesis and tumor progression. Using small molecule inhibition and siRNA strategies, we show that Syk inhibition reduces proliferation and induces apoptosis of PTLD-derived EBV+ B cell lines. Syk inhibition also reduces autocrine IL-10 production. Although Syk inhibition attenuates signaling through both the PI3K/Akt and Erk pathways, only PI3K/Akt inhibition causes apoptosis of PTLD-derived cell lines. Loss of the endogenous caspase inhibitor XIAP is observed after Syk or PI3K/Akt inhibition. The loss of XIAP and apoptosis that results from Syk or PI3K/Akt inhibition is reversed by inhibition of the mitochondrial protease HtrA2. Thus, Syk drives EBV+ B cell lymphoma survival through PI3K/Akt activation, which prevents the HtrA2-dependent loss of XIAP. Syk, Akt, and XIAP antagonists may present potential new therapeutic strategies for PTLD through targeting of EBV-driven survival signals.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / genetics
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Cell Line, Tumor
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Cell Survival
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Epstein-Barr Virus Infections / genetics
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Epstein-Barr Virus Infections / metabolism*
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Epstein-Barr Virus Infections / therapy
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Herpesvirus 4, Human / genetics
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Herpesvirus 4, Human / metabolism*
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High-Temperature Requirement A Serine Peptidase 2
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / metabolism*
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Lymphoma, B-Cell / therapy
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Lymphoma, B-Cell / virology
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MAP Kinase Signaling System*
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA, Small Interfering / genetics
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism*
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Syk Kinase
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X-Linked Inhibitor of Apoptosis Protein / genetics
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X-Linked Inhibitor of Apoptosis Protein / metabolism*
Substances
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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RNA, Small Interfering
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Phosphatidylinositol 3-Kinases
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Proto-Oncogene Proteins c-akt
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Serine Endopeptidases
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HTRA2 protein, human
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High-Temperature Requirement A Serine Peptidase 2