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.