BIOLOGY OF PLASMA CELL TUMOR 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 previously demonstrated that the mechanism by which cytokine independent tumors arise is through constitutive activation of the IL-6 signal transduction pathway. Recent studies have indicated that abl binds directly to the IL-6 receptor. However the receptor is not phosphorylated by abl and the immediate downstream signaling molecules, Jak1 and Jak2, are also unphosphorylated. Abl has been found to directly bind to STAT3, the major signal transducer and activator of transcription in the IL-6 pathway, and subsequent phosphorylation of this molecule leads to constitutive transcriptional activation of the pathway. This system has further been used to evaluate other interactions of abl with regard to possible dysregulation of cellular processes. Abl has been found to interact with molecules in the PI-3 kinase pathway and experiments are currently in progress to determine specific mechanisms by which abl may activate this pathway. 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. One of the major differences between human myeloma and murine plasma cell tumors relates to tissue localization. In early stage disease, myeloma is largely restricted to bone marrow and bone disease is a frequent complication. BALB/c plasma cell tumors are induced in the peritoneal cavity and bone marrow disease and bone involvement have not been evaluated. Current studies have demonstrated that several murine tumors produce bone marrow disease. Detailed analysis of the S107 line demonstrates preferential bone marrow homing in that tumor cells are detected in the marrow at one week following injection, but are absent from other organs. Tumor cells subsequently disseminate to a variety of organs resembling the terminal phase of human disease. Bone destruction associated with osteoclast involvement is observed as tumor cells expand in the marrow. A sub-line has been isolated from the marrow localizing parental tumor which now seeds all organs without preference and thus provides a model to determine the molecular events effecting the ability of tumor cells to disseminate from bone marrow to other organs. The above described similarities between human and murine plasma cell disease suggest that the mouse model is likely to be valuable in developing therapeutic approaches to human disease.