Deregulation of c-Myc in Primary Effusion Lymphoma by KSHV LANA.

Abstract

Primary effusion lymphoma (PEL) is a rare subtype of non-Hodgkin's lymphoma, which is associated with infection by Kaposi's sarcoma herpesvirus (KSHV/HHV-8). PELs lack expression of B-cell markers and rearrangements in common oncogenes. c-Myc is a transcription factor that plays an important role in cellular proliferation, differentiation and apoptosis. Lymphomas frequently have deregulated c-Myc expression due to chromosomal translocations, amplifications or abnormal stabilization. However, no structural abnormalities were found in the c-Myc oncogene in PELs. Given that c-Myc is often involved in lymphomagenesis, we hypothesized that it is deregulated in PELs. We report that PELs have abnormally stable c-Myc protein. Normally, the turnover of c-Myc protein is stringently regulated by post-transcriptional modifications, which include phosphorylation of c-Myc threonine 58 (T58) by glycogen synthase-3 beta (GSK-3 beta). Our data show that the impaired c-Myc degradation in PELs is associated with drastic underphosphorylation of c-Myc T58. The KSHV latency-associated nuclear antigen (LANA) is responsible for this deregulation. Overexpression of LANA in HEK 293 cells leads to abnormal stabilization of c-Myc protein and inhibition of GSK-3 beta-mediated phosphorylation of c-Myc T58. LANA also increases c-Myc protein, but not RNA levels when overexpressed in primary B cells. Conversely, when LANA is eliminated from PELs using RNA interference, there is a post-transcriptional effect leading to a reduction in c-Myc protein. The ability of LANA to prolong the half-life of c-Myc might play an important role in the pathobiology of PEL.