1. ¹Department of Pathology and Laboratory Medicine, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA
2. ²Department of Pathology and Laboratory Medicine, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA
3. ³Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, USA

Correspondence: Associate Professor E Cesarman, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, 1300 York Ave, Room C410, New York, NY, USA. E-mail: ecesarm@med.cornell.edu

Received 17 June 2006; Revised 12 August 2006; Accepted 12 August 2006; Published online 19 February 2007.

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)/human herpesvirus-8. The c-Myc transcription factor plays an important role in cellular proliferation, differentiation and apoptosis. Lymphomas frequently have deregulated c-Myc expression owing to chromosomal translocations, amplifications or abnormal stabilization. However, no structural abnormalities were found in the c-myc oncogene in PEL. Given that c-Myc is often involved in lymphomagenesis, we hypothesized that it is deregulated in PEL. We report that PEL cells have abnormally stable c-Myc protein. The turnover of c-Myc protein is stringently regulated by post-transcriptional modifications, including phosphorylation of c-Myc threonine 58 (T58) by glycogen synthase kinase-3 (GSK-3). Our data show that the impaired c-Myc degradation in PEL cells is associated with a significant underphosphorylation of c-Myc T58. The KSHV latency-associated nuclear antigen (LANA) is responsible for this deregulation. Overexpression of LANA in human embryonic kidney 293 or peripheral blood B cells leads to post-transcriptional deregulation of c-Myc protein. Conversely, when LANA is eliminated from PEL cells using RNA interference, GSK-3-mediated c-Myc T58 phosphorylation is restored. The presence of c-Myc and LANA in GSK-3-containing complexes in PEL cells further confirms the significance of these interactions in naturally KSHV-infected cells.