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 ( approximately 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(Emu) or C.iMyc(Calpha), 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.H2-L(d)-IL6/iMyc(Emu) and C.H2-L(d)-IL6/iMyc(Calpha) 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.
Rutsch
Sebastian
S
Medizinische Klinik V, University of Heidelberg, and National Center for Tumor Diseases, Heidelberg, Germany.
Neppalli
Vishala T
VT
Shin
Dong-Mi
DM
DuBois
Wendy
W
Morse
Herbert C
HC
Goldschmidt
Hartmut
H
Janz
Siegfried
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D016259:Genes, myc; D006801:Humans; D006965:Hyperplasia; D015850:Interleukin-6 / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010950:Plasma Cells / Q000473:pathology; D010954:Plasmacytoma / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D014178:Translocation, Genetic
D000911:Antibodies, Monoclonal; C508600:IL6 protein, human; D015850:Interleukin-6