PLASMACYTOMAGENESIS AND LYMPHOCYTE DEVELOPMENT

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I. Interleukin-6 (IL-6) has been suggested to be the major cytokine involved in the development of plasma cell tumors in both mice and humans. This conclusion is based largely on in vitro studies in which a number of both murine plasmacytoma and human myeloma lines have been shown to be dependent on IL-6 for proliferation. To address the question of the in vivo role of IL-6 in the development of plasma cell neoplasias, we have employed mice carrying a null mutation in the IL-6 gene and thus incapable of producing the corresponding cytokine. Tumor induction studies were conducted using myc/raf or Abl/myc containing retroviruses. Myc/raf containing retroviruses failed to induce plasma cell tumors in mice homozygous for the null allele indicating a complete dependence on IL-6 for tumor induction with these oncogenes. In contrast, Abl/myc induced plasma cell tumors in these same mice at an incidence of 50% indicating that some mutational combinations are likely to induce IL-6 independent tumors. The frequency of occurrence of these two phenotypes will be important in defining preferred therapeutic approaches. II. The metastatic potential of murine plasmacytoma has been examined in an attempt to establish a model for human multiple myeloma which will be of use in the evaluation of therapeutic approaches. Several lines have been identified which produce metastatic disease and infiltrate bone marrow, the primary site of human disease. Cell lines have been infected with retroviruses expressing the Interleukin-2 gene (IL-2) and subsequently injected into animals to assess the occurrence of IL-2 mediated tumor rejection. Initial results indicate significant differences among tumors of the same class in their abilities to induce IL-2 mediated rejection.