Inhibition of the TGFβ Pathway in Primary Effusion Lymphoma.

Kaposi’s sarcoma-associated herpesvirus (KSHV) interferes with a number of cellular pathways involved in apoptosis and cell cycle regulation. Since TGFβ is a potent inducer of cell cycle arrest and apoptosis in hematopoietic lineages, we were interested in examining whether TGFβ signaling is blocked in primary effusion lymphoma (PEL) and if so whether KSHV plays a role in this repression. Treatment with TGFβ1 had no effect on either cell cycle or apoptosis in several PEL cell lines. The defect in this pathway was found to be a lack of the TGFβ type II receptor (TβRII), expression. Upon transfection of TβRII, PEL cell lines become responsive to TGFβ1 treatment. We are currently examining how TβRII transcription is regulated in PEL. The lack of TβRII expression in some tumors has been attributed to altered chromatin structure due to hypoacetylation. Treatment with both a demethylating agent and a histone deacetylase inhibitor resulted in expression of this receptor in PEL. Several KSHV latent gene products are known to interact with or recruit p300, a histone acetyltransferase, for other cellular processes. It is possible that the interaction of one or more of these viral gene products with p300 may serve to prevent it from acetylating histones associated with the TβRII gene and thereby repress its transcription. We have also found by ELISA that PEL cells secrete a higher level of TGFβ1 than other TGF β responsive B cell lines. Increased secretion of TGFβ1 in conjunction with downregulation of TβRII may be a mechanism by which KSHV creates an immunosuppressed environment while allowing infected cells to grow free from the constraints of this pathway.