Deregulation of c-Myc in primary effusion lymphoma by Kaposi's sarcoma herpesvirus latency-associated nuclear antigen

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-3β (GSK-3β). 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-3β-mediated

c-Myc T58 phosphorylation is restored. The presence of c-Myc and LANA in GSK-3β-containing complexes in PEL cells further confirms the significance of these interactions in naturally

KSHV-infected cells.

We thank Rosalie Sears for invaluable advice about the details of c-Myc experiments. This work was supported by NIH Grant R01 CA068939, by a Leukemia and Lymphoma Society Translational

Research Program Grant and by an Irma T Hirschl/Monique Weill-Caulier Career Scientist Award to EC.

Department of Pathology and Laboratory Medicine, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA

Department of Pathology and Laboratory Medicine, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA

Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, USA

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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