ARTICLE ABSTRACTGene-targeted mice that contain a His6-tagged mouse c-Myc cDNA, MycHis, inserted head to head into different sites of the mouse immunoglobulin heavy-chain locus, Igh, mimic the chromosomal T(12;15)(Igh-Myc) translocation that results in the activation of Myc in the great majority of mouse plasmacytomas. Mice carrying MycHis just 5′ of the intronic heavy-chain enhancer Eμ (strain iMycEμ) provide a specific model of the type of T(12;15) found in a subset (∼20%) of plasmacytomas that develop “spontaneously” in the gut-associated lymphoid tissue (GALT) of interleukin-6 transgenic BALB/c (C) mice. Here we show that the transfer of the iMycEμ transgene from a mixed genetic background of segregating C57BL/6 × 129/SvJ alleles to the background of C increased the incidence of GALT plasmacytomas by a factor of 2.5 in first-generation backcross mice (C.iMycEμ N1). Third-generation backcross mice (C.iMycEμ N3, ∼94% C alleles) were hypersusceptible to inflammation-induced peritoneal plasmacytomas (tumor incidence, 100%; mean tumor onset, 86 ± 28 days) compared with inbred C mice (tumor incidence, 5% on day 150 after tumor induction). Peritoneal plasmacytomas of C.iMycEμ N3 mice overexpressed MycHis, produced monoclonal immunoglobulin, and exhibited a unique plasma cell signature upon gene expression profiling on mouse Lymphochip cDNA microarrays. These findings indicated that the iMycEμ transgene accelerates plasmacytoma development by collaborating with tumor susceptibility alleles of strain C and circumventing the requirement for tumor precursors to acquire deregulated Myc by chromosomal translocation.