Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma

Oncogene. 2006 Feb 16;25(7):998-1007. doi: 10.1038/sj.onc.1209147.

Abstract

Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by overexpression of cyclin D1 due to the t(11;14) chromosomal translocation. While expression of cyclin D1 correlates with MCL development, expression of wild-type (WT) cyclin D1 transgene in murine lymphocytes is unable to drive B-cell lymphoma. As cyclin D1 mutants that are refractory to nuclear export display heighten oncogenicity in vitro compared with WT D1, we generated mice expressing FLAG-D1/T286A, a constitutively nuclear mutant, under the control of the immunoglobulin enhancer, Emu. D1/T286A transgenic mice universally develop a mature B-cell lymphoma. Expression of D1/T286A in B lymphocytes results in S phase entry in resting lymphocytes and increased apoptosis in spleens of young premalignant mice. Lymphoma onset correlates with perturbations in p53/MDM2/p19Arf expression and with BcL-2 overexpression suggesting that alterations in one or both of these pathways may contribute to lymphoma development. Our results describe a cyclin D1-driven model of B-cell lymphomagenesis and provide evidence that nuclear-retention of cyclin D1 is oncogenic in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • B-Lymphocytes / metabolism*
  • Cell Nucleus / metabolism
  • Cyclin D1 / genetics*
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase 4 / metabolism
  • Immunoglobulin M / analysis
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, B-Cell / immunology
  • Lymphoma, Mantle-Cell / genetics*
  • Lymphoma, Mantle-Cell / immunology
  • Mice
  • Mice, Transgenic
  • Mutation
  • S Phase

Substances

  • Immunoglobulin M
  • Cyclin D1
  • Cyclin-Dependent Kinase 4