Multiple Myeloma— Another Role for KSHV?

ABSTRACT & COMMENTARY

Synopsis: Kaposi’s sarcoma-associated herpesvirus (KSHV, HHV-8) genome was detected in bone marrow stromal dendritic cells, but not in malignant cells of patients with multiple myeloma. It is hypothesized that KSHV is involved in the pathogenesis of multiple myeloma by local production in the marrow of IL-6, which is necessary for the growth and survival of myeloma cells.

Source: Rettig MB, et al. Kaposi’s sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients. Science 1997;276:1851-1854.

Rettig and colleagues at ucla examined individual preparations of bone marrow mononuclear cells and bone marrow dendritic cells of patients with multiple myeloma and controls for evidence of KSHV DNA by polymerase chain reaction. Each sample tested contained approximately 100 ng DNA, representing the DNA from approximately 15,000 cells. While KSHV DNA was not detected in any of the marrow mononuclear cell samples (containing 11%-90% malignant plasma cells) from any of 23 myeloma patients, it was detected in marrow stroma samples of all 15 myeloma patients studied. KSHV sequences were also detected in the marrow stromal cells of two of eight patients with monoclonal gammopathy of undetermined significance (MGUS). KSHV sequence was not detected in marrow stromal or mononuclear cell preparations of any of 19 healthy controls, or of 14 subjects with lymphoma, one with acute myelogenous leukemia, or one with adenocarcinoma. Evaluation of surface markers indicated that the affected stromal cells were dendritic cells.

Further analysis demonstrated the presence of RNA transcripts of the viral homolog of human IL-6, vIL-6, in three of three myeloma bone marrow stromal cell samples, but in neither of two samples from healthy controls.

COMMENT BY STAN DERESINSKI, MD, FACP

Multiple myeloma is a disease in which there is an uncontrolled proliferation of plasma cells with the production of monoclonal immunoglobulin. It is reported to affect 0.15% of the population.1

Myeloma cells express receptors for IL-6. Their growth and survival are dependent upon this cytokine—the latter, at least in part, by inhibition of apoptosis.2,3 Endogenous IL-6 production is 2-30 times higher in multiple myeloma patients than in healthy controls.4

Previous studies have found that the source of this IL-6 in vivo is not the malignant cells themselves, but the non-malignant bone marrow stromal cells, which thus act to stimulate neoplastic growth in a paracrine fashion.2 Bone marrow stroma, which is comprised of fibroblasts, macrophages, and endothelial cells, provides the necessary microenvironment, via both direct cell contact and cytokine production, for normal hematopoiesis. Dendritic cells, derived from macrophages, play a critical role in B cell growth and differentiation, as well as in maximizing the amount of IgG and IgA produced by these cells.5

KSHV, like other herpes viruses, has, over the millennia, captured a number of human genes, and, as a consequence, this virus has nine open reading frames that encode homologs of human proteins. These proteins include not only vIL-6, but also two macrophage inhibitory proteins (vMIP-1a, vMIp-1b), BCK, IL-8 receptor, thymidylate synthetase and dihydrofolate reductase, bcl-2 (an anti-apoptotic protein), interferon regulatory factors, and v-cyclin (which increases cell cycling).6,7 Many of these viral products, including vIL-6, have been demonstrated to be biologically active upon human cells.8

These findings suggest that patients with AIDS ought to have an increased incidence of multiple myeloma, something for which there is no evidence. They do, however, have an approximately 15% incidence of monoclonal gammopathy, which in some non-AIDS patients may be a harbinger of the development of multiple myeloma.9

The role of IL-6 as a neoplastic growth factor is not unique to multiple myeloma. As the authors point out, IL-6 is a growth factor for at least three other KSHV-related diseases: Kaposi’s sarcoma, pleural effusion, and multicentric Castleman’s disease.

The findings discussed here are intriguing and raise the possibility that KSHV has a pathogenic role, most likely as a cofactor, in multiple myeloma.

References

1. Bataille R, Harousseau JL. Multiple Myeloma 1997; 336:1657-1664.

2. Klein B, et al. Blood 1989;73:517-526.

3. Hardin J, et al. Blood 1994;84:3063-3070.

4. van Zaanen HC, et al. J Clin Invest 1996;98: 1441-1448.

5. Dubois B, et al. J Exp Med 1997;185:941-951.

6. Russo JJ, et al. Proc Natl Acad Sci USA. 1996; 93:14862-14867.

7. Nicholas J, et al. J Virol 1997;71:1963-1974.

8. Moore PS, et al. Science 1996;274:1739-1744.

9. Gold JE, et al. Cancer 1990;66:363-368.