PLASMACYTOMAGENESIS AND LYMPHOCYTE DEVELOPMENT

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I. Interleukin-6 (IL-6) has been demonstrated to be the major growth factor involved in development of murine plasma cell tumors and human myeloma. Mice in which the IL-6 gene has been inactivated are resistant to tumor induction as evidenced by the failure of tumors to develop following treatment with retroviruses containing raf and myc oncogenes. However, these mice develop tumors when raf is replaced by abl, suggesting that IL-6 independent tumors can be generated either by other oncogene combinations or mutations. We have examined the mechanism by which cytokine independent tumors arise through an analysis of the IL-6 signal transduction pathway. Binding of IL-6 to its receptor leads to activation of a protein cascade resulting in induction of new gene expression and cell growth. The major transcription activating factor in this cascade, designated STAT 3, was evaluated in plasma cell tumors induced by chemical agents or oncogenes including raf/myc and abl/myc. Results indicate that the IL-6 pathway is inducible in chemical and raf/myc tumors, but constitutively activated by abl/myc as evidenced by phosphorylation of STAT 3 in either the presence or absence of cytokine. The constitutive activation of cytokine signaling pathways may be a general mechanism by which many oncogenes subvert normal cell growth regulation. II. Studies have continued on the development of a model for human myeloma using mouse plasma cell tumors to evaluate gene therapy approaches to disease treatment. Introduction of the Interleukin-2 (IL-2) gene into plasma cell lines results in varying degrees of rejection associated with individual tumors following re-introduction into animals. Recent experiments employing irradiated, IL-2 secreting cells reveals a significant degree of protection in 2/2 lines following challenge with parental cells suggesting that these cells may be effective in generating an anti-tumor response capable of inducing tumor rejection.