Comment on Baumforth et al, page 2138
Baumforth and colleagues provide evidence implicating Epstein-Barr virus (EBV)-induced up-regulation of autotaxin expression in Hodgkin and Reed-Sternberg (HRS) cells in the pathogenesis of Hodgkin lymphoma (HL).
The observation that a proportion of Hodgkin lymphoma (HL) cases are associated with Epstein-Barr virus (EBV) has represented a landmark for research into HL. Monoclonal EBV genomes were detected in all Hodgkin and Reed-Sternberg (HRS) cells of EBV-associated HL, providing evidence of the clonal nature of HRS cells.1 Furthermore, this finding has provided the rationale for current efforts to use EBV-specific T cells for the treatment of HL.2
It has been difficult, however, to define the role EBV plays in HL pathogenesis. This is partly because there is only one EBV+ HL-derived cell line, L591, that shows a pattern of EBV gene expression (latency III: Epstein-Barr nuclear antigen-1 positive [EBNA1+], EBNA2+, latent membrane protein 1 positive [LMP1+], LMP2+) distinct from that observed in HRS cells in vivo (latency II: EBNA1+, EBNA2-, LMP1+, LMP2+). Studies of biopsy material have provided circumstantial evidence for a causal role of EBV—for example, by demonstrating phenotypic differences between EBV+ and EBV- HRS cells.
In this issue of Blood, Baumforth and colleagues have generated an EBV-infected subline of an EBV- HL-derived cell line, KM-H2. Again, this cell line shows an unorthodox pattern of viral gene expression (EBNA1+, EBNA2+, LMP1-, LMP2+). Nevertheless, this model has enabled the authors to study the effects of EBV infection in HRS cells directly. Among differentially expressed genes, autotaxin was identified as being strongly up-regulated in the EBV+ KM-H2 cells. This observation was confirmed by a reverse approach: an EBV- subclone of the EBV+ L591 cell line showed down-regulation of autotaxin expression. The effect of EBV on autotaxin expression appears to be dependent on cell lineage, since it was not observed in EBV-associated Burkitt lymphoma or nasopharyngeal carcinoma. Autotaxin is an autocrine motility-stimulating factor promoting cell migration, metastasis, and angiogenesis.3 Autotaxin functions as a lysophospholipase D, catalyzing the generation of lysophosphatidic acid (LPA) and sphyngosine-1-phosphate (S1P). LPA mediates most of the effects ascribed to autotaxin by interaction with endothelial cell differentiation gene (EDG) receptors.4
Baumforth et al show that EBV-induced up-regulation of autotaxin expression in KM-H2 cells is accompanied by increased secretion of autotaxin and increased LPA production in supernatants and that this change is associated with enhanced proliferation and survival of HRS cells. The relevance of these findings for HL pathogenesis is emphasized by the demonstration that high-level autotaxin expression in HRS cells in vivo is associated with EBV infection of tumor cells.
Several questions remain to be addressed. It will be important to determine which viral protein is responsible for the up-regulation of autotaxin. The obvious candidate, LMP1, is excluded because it is not expressed in these cells. It also remains uncertain which receptor mediates the effects of LPA on HRS cells. The sole EDG receptor detected in KM-H2 cells, EDG1, is a receptor for S1P but not for LPA, suggesting that as-yet-unidentified receptors may be relevant. This is important because EDG receptor antagonists are currently being developed and may have therapeutic use in HL.3 Autotaxin may produce another regulator of migration, S1P, which affects lymphocyte trafficking, promoting retention of lymphocytes in lymph nodes.5 Although S1P was not detected in KM-H2 supernatants, it is tempting to speculate that this mechanism might contribute to the abundance of lymphocytes characteristically present in HL tissues.
In summary, Baumforth et al add a new and unexpected member to the list of EBV-induced gene products and strengthen the notion that EBV is involved in the pathogenesis of HL. ▪