In 2015, we took advantage of a mouse that expresses IL6 at high levels in most cell types from an IL6 transgene and develops a high incidence of IL6-dependent plasma cell neoplasms, termed plasmacytomas (PCT), with some similarities to human multiple myeloma (MM). MM, like other malignancies of the B cell lineage, is an incurable disease in humans due in large part to the support for the tumor cells provided by the tumor microenvironment. Overcoming this support is a major goal of tumor treatment. Since IL6 is critical for PCT growth in the transgenic mice, we asked if tumorigenesis was dependent on autocrine IL6 produced by the PCT or by paracrine expression from the microenvironment in which the tumors developed. The results demonstrate that paracrine expression of IL6 was critical for PCT development while autocrine expression was dispensable. These findings suggest the potential importance of the IL6 signaling pathway as target for inhibiting pre-neoplastic plasma cell expansion in various autoimmune and inflammatory diseases that can be complicated by the development of plasma cell neoplasms. In previous studies, we showed that B cell lymphomas developed at high frequencies in mice with B cells made deficient in expression of TRAF3, a critical component of the signaling pathway downstream of CD40 that promotes cell proliferation and survival. We extended these studies this year by asking what the effects of TRAF3-deficiency in macrophages might be. Unexpectedly, the mice were found to have chronic inflammatory lesions, a variety of tumor types including B cell lymphomas, histiocytic sarcomas and liver tumors and were immunodeficient in having a variety of infections. These findings emphasize the importance of TRAF3 signaling to innate as well as adaptive immunity and suggest that altered expression of TRAF3 might contribute to similar conditions in humans. Finally, we continue to be active in efforts to improve the classification systems for mouse hematopoietic neoplasms as they relate to similar human neoplasms. It is important for pathologists to be able to discriminate between hematopoietic neoplasms and non-malignant reactive lesions in the mouse and we have developed guidelines for making these determinations.
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