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

• Published in: American journal of transplantation Vol. 13; no. 4; pp. 883 - 890
• Main Authors: Hatton, O., Lambert, S. L., Phillips, L. K., Vaysberg, M., Natkunam, Y., Esquivel, C. O., Krams, S. M., Martinez, O. M.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley 01.04.2013; Elsevier Limited
• Subjects: Aminopyridines; Animals; Apoptosis; B-Lymphocytes - metabolism; Biological and medical sciences; Cell Cycle; Cell Line, Tumor; Enzyme Activation; Epstein-Barr virus; Epstein-Barr Virus Infections - enzymology; Hematologic and hematopoietic diseases; Herpesvirus 4, Human; Humans; Infectious diseases; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymph Nodes - pathology; Lymphoma; Lymphoma, B-Cell - enzymology; Lymphoma, B-Cell - virology; Lymphoproliferative Disorders - enzymology; Lymphoproliferative Disorders - virology; Male; Medical research; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Morpholines; Oxazines - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; PI‐3‐kinase/Akt pathway; Postoperative Complications; posttransplant lymphoproliferative disorder; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; PTLD; Pyridines - pharmacology; Pyrimidines; Signal Transduction; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Syk Kinase; Transplantation, Heterologous; Viral diseases; Gammaherpesvirinae; Enzyme; Herpesviridae; Transferases; Akt protein kinase; Hemopathy; Activation; Epstein Barr virus; PI-3-kinase/Akt pathway; Epstein―Barr virus; 1-Phosphatidylinositol 3-kinase; Infection; Virus; Posttransplant lymphoproliferative disorder; Lymphoproliferative syndrome; Viral disease; PTLD; Tyrosine protein kinase Syk; Protein-tyrosine kinase
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.12137

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. The authors demonstrate that small molecule inhibition of the PI3K/Akt pathway reduces tumor formation and tumor burden in a xenotransplantation model of Epstein—Barr virus—positive posttransplant lymphoproliferative disorder.