Oncogene-induced senescence as an initial barrier in lymphoma development

Melanie Braig, Soyoung Lee, Christoph Loddenkemper, Cornelia Rudolph, Antoine H.F.M. Peters, Brigitte Schlegelberger, Harald Stein, Bernd Dörken, Thomas Jenuwein and Clemens A. Schmitt ()
Additional contact information
Melanie Braig: Charité – Universitätsmedizin Berlin/Haematology-Oncology
Soyoung Lee: Charité – Universitätsmedizin Berlin/Haematology-Oncology
Christoph Loddenkemper: Charité – Universitätsmedizin Berlin/Department of Pathology
Cornelia Rudolph: Hannover Medical School
Antoine H.F.M. Peters: Friedrich Miescher Institute for Biomedical Research
Brigitte Schlegelberger: Hannover Medical School
Harald Stein: Charité – Universitätsmedizin Berlin/Department of Pathology
Bernd Dörken: Charité – Universitätsmedizin Berlin/Haematology-Oncology
Thomas Jenuwein: Research Institute of Molecular Pathology
Clemens A. Schmitt: Charité – Universitätsmedizin Berlin/Haematology-Oncology

Nature, 2005, vol. 436, issue 7051, 660-665

Abstract: 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 Eµ-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.

Date: 2005
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DOI: 10.1038/nature03841

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