1. Charité – Universitätsmedizin Berlin/Haematology-Oncology, 13353 Berlin, Germany
2. Charité – Universitätsmedizin Berlin/Department of Pathology, 12200 Berlin, Germany
3. Institute of Cell and Molecular Pathology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
4. Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland
5. Research Institute of Molecular Pathology, 1030 Vienna, Austria
6. Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany

Correspondence to: Clemens A. Schmitt^1,6 Correspondence and requests for materials should be addressed to C.A.S. (Email: clemens.schmitt@charite.de).

Abstract

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 E-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.

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