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Insertion of Myc into Igh Accelerates Peritoneal Plasmacytomas in Mice

¹ Laboratory of Genetics and ² Metabolism Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Siegfried Janz, Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, Room 3140A, Building 37, Bethesda, MD 20892-4256. Phone: 301-496-2202; Fax: 301-402-1031; E-mail: sj4s{at}nih.gov.

Gene-targeted mice that contain a His⁶-tagged mouse c-Myc cDNA, Myc^His, 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 Myc^His just 5' of the intronic heavy-chain enhancer Eµ (strain iMyc^Eµ) 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 iMyc^Eµ transgene from a mixed genetic background of segregating C57BL/6 x 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.iMyc^Eµ N₁). Third-generation backcross mice (C.iMyc^Eµ 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.iMyc^Eµ N₃ mice overexpressed Myc^His, produced monoclonal immunoglobulin, and exhibited a unique plasma cell signature upon gene expression profiling on mouse Lymphochip cDNA microarrays. These findings indicated that the iMyc^Eµ 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.

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