Oncogene-induced senescence as an initial barrier in lymphoma development

Nature. 2005 Aug 4;436(7051):660-5. doi: 10.1038/nature03841.


Acute induction of oncogenic Ras provokes cellular senescence involving the retinoblastoma (Rb) pathway, but the tumour suppressive potential of senescence in vivo remains elusive. Recently, Rb-mediated silencing of growth-promoting genes by heterochromatin formation associated with methylation of histone H3 lysine 9 (H3K9me) was identified as a critical feature of cellular senescence, which may depend on the histone methyltransferase Suv39h1. Here we show that Emicro-N-Ras transgenic mice harbouring targeted heterozygous lesions at the Suv39h1, or the p53 locus for comparison, succumb to invasive T-cell lymphomas that lack expression of Suv39h1 or p53, respectively. By contrast, most N-Ras-transgenic wild-type ('control') animals develop a non-lymphoid neoplasia significantly later. Proliferation of primary lymphocytes is directly stalled by a Suv39h1-dependent, H3K9me-related senescent growth arrest in response to oncogenic Ras, thereby cancelling lymphomagenesis at an initial step. Suv39h1-deficient lymphoma cells grow rapidly but, unlike p53-deficient cells, remain highly susceptible to adriamycin-induced apoptosis. In contrast, only control, but not Suv39h1-deficient or p53-deficient, lymphomas senesce after drug therapy when apoptosis is blocked. These results identify H3K9me-mediated senescence as a novel Suv39h1-dependent tumour suppressor mechanism whose inactivation permits the formation of aggressive but apoptosis-competent lymphomas in response to oncogenic Ras.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / metabolism
  • Animals
  • Apoptosis / drug effects
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / metabolism
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology*
  • Cellular Senescence* / drug effects
  • Cellular Senescence* / genetics
  • Chromosomal Instability / genetics
  • Disease Models, Animal
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Genes, ras / genetics*
  • Heterochromatin / genetics
  • Heterochromatin / metabolism
  • Lymphoma / genetics*
  • Lymphoma / metabolism
  • Lymphoma / pathology*
  • Methylation
  • Methyltransferases / deficiency
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Mice
  • Mice, Transgenic
  • Precancerous Conditions / genetics
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Transgenes / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • Biomarkers, Tumor
  • Heterochromatin
  • Repressor Proteins
  • Tumor Suppressor Protein p53
  • Suv39h1 protein, mouse
  • Methyltransferases
  • ADP-Ribosylation Factors