The role of interleukin-3 and stem cell factor in classical Hodgkin disease

We have read with great interest the comprehensive review by Skinnider and Mak that summarizes the current literature regarding the expression and activity of cytokines in classical Hodgkin disease (cHD), a unique pathologic condition in which a minority of clonal neoplastic cells are embedded in a heterogeneous background of nonmalignant cells.1 As stated by the authors, given the peculiar features of HD, bona fide HD-derived cell lines remain to date invaluable tools for investigating the cytokine-dependent interactions of Hodgkin–Reed Sternberg (H-RS) cells. Nevertheless, information from these studies should be always confirmed and validated by other studies carried out in the context of fresh HD-involved tissues or involving primary H-RS cells. By using such an approach, we have described 2 cytokine circuitries allegedly operating in HD that involve interleukin-3 (IL-3), stem cell factor (SCF), and their corresponding receptors (Rs).2-5 

As opposed to data reported by Skinnider and Mak,1 our evidence seems to suggest a role for IL-3 in H-RS cell proliferation and survival.2 In this regard, we demonstrated that IL-3 can promote the clonogenic growth of HD-derived cells and is able to partially rescue them from apoptosis induced by serum deprivation.2 Accordingly, HD-derived cell lines express mRNA and protein of the IL-3Rαβ complex, whereas primary H-RS cells from all cHD cases tested can be stained by anti–IL-3Rα antibodies.2 

On the other hand, data reported by Skinnider and Mak indicating the lack of IL-3 production by HD-derived cell lines1 are consistent with our findings obtained by using a technical approach as sensitive as reverse transcriptase–polymerase chain reaction.2 

Moreover, the notion that IL-3 mRNA was detected by Northern analysis in some cases of cHD-involved tissues, as reported by Skinnider and Mak,1 is in keeping with data from our group demonstrating the ability of HD-derived cells to modulate the production of IL-3 by T cells.3 In fact, preactivated purified T cells, when cultured along with paraformaldehyde-fixed HD-derived cells, release significantly higher amounts of IL-3 than in cultures carried out without fixed HD-derived cells.3 

The expression of SCF receptor (SCFR)/c-kit by the neoplastic component of cHD has been described by us some years ago.4 This data, given the notion that fibrosis is a common feature of cHD-involved tissues6 and SCF is produced by several stomal cells including fibroblasts,7strongly suggested a role of SCF/SCFR pair in cHD. The formal proof of this has been recently provided.5 By using HD-derived cell lines and fibroblasts from HD-involved lymph nodes (HDF), we demonstrated the expression of c-kit in HD-derived cells and of SCF in primary HDF.5 Moreover, functional experiments have shown the in vitro adhesion of HD-derived cells to HDF through c-kit/SCF interactions, as well as the capability of SCF to increase the growth/survival of HD-derived cells, and to partially rescue HD-derived cells from apoptosis induced by serum starvation.5 

To improve the knowledge of the various cytokine pathways sustaining H-RS cell proliferation and survival may eventually contribute to the design of innovative therapies for relapsed/refractory HD patients.