Kinase Lynks to herpesvirus lymphomagenesis

Comment on Prakash et al, page 3987

A relationship between Src family kinases and KSHV lymphomagenesis revealed.

Prakash and colleagues have reported previously the development of plasmablastic lymphomas (with resultant establishment of a “KVL-1” cell line) and increased Lyn kinase activity in a transgenic mouse model expressing the K1 gene of the Kaposi sarcoma–associated herpesvirus (KSHV).¹  In this issue of Blood, they offer compelling data linking K1 gene expression, Lyn kinase activation, and lymphomagenesis using several elegant in vitro and in vivo experiments. Inhibition of nuclear factor κB (NF-κB) promoter activity, vascular endothelial growth factor (VEGF) production, thymidine incorporation, and proliferation of KVL-1 cells is achieved with the Lyn kinase inhibitor protein phosphatase 2 (PP2) but not an inhibitor of Syk tyrosine kinase. Separate mouse and human B-cell tumor lines expressing K1 showed an increase in phosphorylation of Lyn, activity of the NF-κB promoter, and production of VEGF compared with cells expressing K1 mutants, whereas VEGF promoter activity in K1-expressing cells was reduced with PP2. Finally, treatment of K1 transgenic mice with either anti-VEGF antibodies or an inhibitor of NF-κB phosphorylation independently decreased serum VEGF levels and inhibited in situ tumor growth in this model, supporting the potential importance of both pathways for KSHV lymphomagenesis.

The importance of Src family kinases, and Lyn kinase specifically, for hematopoietic tumorigenesis has been demonstrated for other human malignancies, including B-cell leukemias.²  But via what pathways does KSHV K1-related Lyn kinase expression influence tumorigenesis? While Prakash et al corroborated earlier work using KSHV G protein–coupled receptor (vGPCR)–transfected cells that showed inhibition of both VEGF and NF-κB upregulation with an inhibitor for the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway,³  use of the same inhibitor with K1-transfected cells abrogated VEGF production but not NF-κB promoter activity. This supports the notion that KSHV-related lymphomagenesis results from the expression of multiple viral oncogenes and manipulation of different intracellular signaling pathways.

Which of these pathways plays a more important role in KSHV-related tumorigenesis? Why do some patients exhibit the more common clinical manifestation of KSHV infection, Kaposi sarcoma, rather than lymphoma? Furthermore, how does KSHV manipulate hematopoietic cell machinery and immune responses to escape detection and allow for broader gene expression and tumorigenesis? In vitro studies and transgenic models have clearly advanced our understanding of molecular mechanisms for KSHV-related immune evasion⁴  and cell signaling¹  while helping to identify potential therapeutic targets for KSHV-related tumors. A movement toward the development of viable therapies and means of prevention for these tumors whose pathogenesis remains complex likely depends upon model systems incorporating the entire viral genome, multiple potential human cell targets for KSHV infection, and intact immunity. ▪