IL-6 and MYC collaborate in plasma cell tumor formation in mice

Interleukin-6 (IL-6) plays a critical role in the natural history of human plasma cell neoplasms (PCNs), such as plasma cell myeloma and plasmacytoma (PCT). IL-6 is also at the center of neoplastic plasma cell transformation in BALB/c (C) mice carrying a transgene, H2-L-d-IL6, that encodes human IL-6 under control of the major histocompatibility complex H2-L-d promoter: strain C. H2-L-d-IL6. These mice are prone to PCT, but tumor development is incomplete with long latencies (similar to 40% PCT at 12 months of age). To generate a more robust mouse model of IL-6-dependent PCN, we intercrossed strain C.H2-L-d-IL6 with strains C.iMyc(E mu) or C.iMyc(C alpha), 2 interrelated gene-insertion models of the chromosomal T(12; 15) translocation causing deregulated expression of Myc in mouse PCT. Deregulation of MYC is also a prominent feature of human PCN. We found that double-transgenic C.H2L(d)-IL6/iMyc(E mu) and C.H2-L-d-IL6/iMyc(C alpha) mice develop PCT with full penetrance (100% tumor incidence) and short latencies (3-6 months). The mouse tumors mimic molecular hallmarks of their human tumor counterparts, including elevated IL-6/Stat3/Bcl-X-L signaling. The newly developed mouse strains may provide a good preclinical research tool for the design and testing of new approaches to target IL-6 in treatment and prevention of human PCNs. (Blood. 2010;115:1746-1754)