ABSTRACT
Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus that is the etiological agent of the endothelial cell cancer Kaposi's sarcoma (KS) and 2 B cell lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KSHV ORF36, also known as viral protein kinase (vPK), is a viral serine/threonine kinase. We previously reported that KSHV vPK enhances cell proliferation and mimics cellular S6 kinase to phosphorylate ribosomal protein S6, a protein involved in protein synthesis. We created a mouse model to analyze the function of vPK in vivo. We believe this is the first mouse tumor model of a viral kinase encoded by a pathogenic human virus. We observed increased B cell activation in the vPK transgenic mice compared with normal mice. We also found that, over time, vPK transgenic mice developed a B cell hyperproliferative disorder and/or a high-grade B cell non-Hodgkin lymphoma at a greatly increased incidence compared with littermate controls. This mouse model shows that a viral protein kinase is capable of promoting B cell activation and proliferation as well as augmenting lymphomagenesis in vivo and may therefore contribute to the development of viral cancers.
Subject(s)
Cell Transformation, Viral , Herpesvirus 8, Human/enzymology , Lymphoma, Primary Effusion/enzymology , Neoplasm Proteins/metabolism , Protein Kinases/metabolism , Animals , Castleman Disease/enzymology , Castleman Disease/genetics , Castleman Disease/pathology , Castleman Disease/virology , Herpesvirus 8, Human/genetics , Humans , Lymphoma, Primary Effusion/genetics , Lymphoma, Primary Effusion/pathology , Lymphoma, Primary Effusion/virology , Mice , Mice, Transgenic , Neoplasm Proteins/genetics , Protein Kinases/geneticsABSTRACT
BACKGROUND: A 34-year-old male presented with a 5-month history of fatigue, anorexia, low fever, night sweats, and oliguria with edema of the eyelid, exacerbated by abdominal distension and mild diarrhea of 3 weeks duration. Physical examination showed positive signs of ascites, palpable spleen, slight abdominal tenderness and mild rebound tenderness in the lower abdomen, and edema of the lower limbs. Initial laboratory tests revealed abnormal liver biochemistry and increased protein concentration in the urine. Chest X-ray showed minimal pleural effusion in both sides of the thoracic cavity, and ultrasound detected moderate ascites, several small lymph nodes in the retroperitoneum, and mild splenomegaly with widening of the splenic vein. A lymph node biopsy established the diagnosis, and cytokine analysis in the serum revealed COX2 as the possible mediator. INVESTIGATIONS: Abdominal paracentesis, chest X-ray, abdominal ultrasound, thoracic and abdominal CT scans, gastroscopy, colonoscopy, biopsies of the liver, bone marrow and lymph nodes, immunophenotype staining for lymphocytes, cytokine analysis. DIAGNOSIS: COX2-related multicentric mixed-type Castleman's disease. MANAGEMENT: Chemotherapy and COX2 inhibitors.
