Oncogene-induced senescence as an initial barrier in lymphoma development

• Published in: Nature Vol. 436; no. 7051; pp. 660 - 665
• Main Authors: Schmitt, Clemens A, Braig, Melanie, Lee, Soyoung, Loddenkemper, Christoph, Rudolph, Cornelia, Peters, Antoine H.F.M, Schlegelberger, Brigitte, Stein, Harald, Dörken, Bernd, Jenuwein, Thomas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 04.08.2005; Nature Publishing Group
• Subjects: ADP-Ribosylation Factors - metabolism; Animal tumors. Experimental tumors; Animals; Apoptosis - drug effects; Biological and medical sciences; Biomarkers, Tumor - analysis; Biomarkers, Tumor - metabolism; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cellular biology; Cellular Senescence - drug effects; Cellular Senescence - genetics; Chromosomal Instability - genetics; Disease Models, Animal; Disease Progression; Experimental malignant blood diseases; Gene Expression Regulation, Neoplastic; Genes; Genes, ras - genetics; Heterochromatin - genetics; Heterochromatin - metabolism; Inactivation; Lymphocytes; Lymphoma; Lymphoma - genetics; Lymphoma - metabolism; Lymphoma - pathology; Medical sciences; Methylation; Methyltransferases - deficiency; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Mice, Transgenic; Oncology; 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; Tumors; Senescence; Rodentia; Malignant hemopathy; Carcinogenesis; Lymphoma; Vertebrata; Mammalia; Mouse; Lymphoproliferative syndrome; Animal; C-Onc gene; T-Lymphocyte; Genetics; Ras gene; Protooncogene
• ISSN: 0028-0836; 1476-4687
• 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.