Insertion of Myc into Igh accelerates peritoneal plasmacytomas in mice.
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 Emu (strain iMyc(Emu)) provide a specific model of the type of T(12;15) found in a subset (approximately 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(Emu) 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(Emu) N1). Third-generation backcross mice (C.iMyc(Emu) N3, approximately 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(Emu) 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(Emu) 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.
Park
Sung Sup
SS
Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4256, USA.
Shaffer
Arthur L
AL
Kim
Joong Su
JS
duBois
Wendy
W
Potter
Michael
M
Staudt
Louis M
LM
Janz
Siegfried
S
D000483:Alleles; D000818:Animals; D015870:Gene Expression; D005803:Genes, Immunoglobulin / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics*; D008221:Lymphoid Tissue / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000473:pathology; D010954:Plasmacytoma / Q000235:genetics* / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D019076:Transgenes / Q000235:genetics