title: Oncogene-induced senescence as an initial barrier in lymphoma development.
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 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.
authors.affiliation: Charité-Universitätsmedizin Berlin/Haematology-Oncology, 13353 Berlin, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Braig
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Cornelia
authors.initials: C
authors.lastname: Rudolph
authors.forename: Antoine H F M
authors.initials: AH
authors.lastname: Peters
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Harald
authors.initials: H
authors.lastname: Stein
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Thomas
authors.initials: T
authors.lastname: Jenuwein
authors.forename: Clemens A
authors.initials: CA
authors.lastname: Schmitt
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008745:Methylation; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D006570:Heterochromatin; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases; D020727:ADP-Ribosylation Factors