Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice

J Clin Invest. 2004 Jun;113(12):1763-73. doi: 10.1172/JCI20369.

Abstract

Deregulated expression of both Myc and Bcl-X(L) are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and Bcl-X(L) in mouse plasma cells might lead to an improved model of human PCN, we generated Myc transgenics by inserting a single-copy histidine-tagged mouse Myc gene, Myc(His), into the mouse Ig heavy-chain Calpha locus. We also generated Bcl-X(L) transgenic mice that contain a multicopy Flag-tagged mouse Bcl-x(Flag) transgene driven by the mouse Ig kappa light-chain 3' enhancer. Single-transgenic Bcl-X(L) mice remained tumor free by 380 days of age, whereas single-transgenic Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast, double-transgenic Myc/Bcl-X(L) mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). These tumors produced monoclonal Ig, infiltrated the bone marrow, and contained elevated amounts of Myc(His) and Bcl-X(L)(Flag) proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-X(L) mice. Our findings demonstrate that the enforced expression of Myc and Bcl-X(L) by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates some features of human multiple myeloma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / metabolism
  • Bone Marrow / pathology
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lymph Nodes / cytology
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Plasmacytoma / genetics
  • Plasmacytoma / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Spleen / cytology
  • Spleen / metabolism
  • Spleen / pathology
  • bcl-X Protein

Substances

  • Antibodies, Monoclonal
  • BCL2L1 protein, human
  • Bcl2l1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • bcl-X Protein