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 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.

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Figure 1: Suv39h1 - and p53 -defects license aggressive lymphomas in response to oncogenic Ras.
Figure 2: Oncogenic Ras selects against Suv39h1, ARF or p53 in primary lymphomas.
Figure 3: Suv39h1 loss produces chromosomally stable senescence-defective, but apoptosis-competent, Ras lymphomas.
Figure 4: Suv39h1/H3K9me-controlled senescence limits Ras-mediated oncogenicity.
Figure 5: Methylation-targeting therapy mimics Suv39h1 loss in a Ras transgenic context in vivo.

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Acknowledgements

We thank A. Harris, T. Jacks and M. Serrano for mice; S. W. Lowe for retroviral constructs; B. Teichmann and S. Spieckermann for technical assistance; and A. Lee, M. Reimann and P. Kahlem for discussions and editorial advice. This work was supported by grants from the European Union (to B.S.) and from the Deutsche Krebshilfe (to C.A.S.). S.L. is a postdoctoral fellow of the José Carreras Leukemia Foundation.

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Correspondence to Clemens A. Schmitt.

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Supplementary information

Supplementary Figure S1

Characterization of Ras-induced neoplasms. (PDF 21776 kb)

Supplementary Figure S2

Representative dual-colour flow cytometric analyses of the indicated antigens reflecting the haematopoietic differentiation status in different haematopoietic compartments of Suv39h1+/+ and Suv39h1-/- mice of matched age. (PDF 33 kb)

Supplementary Figure S3

Invasiveness, growth characteristics and expression of related genes in mouse embryo fibroblasts and Ras-driven lymphomas. (PDF 38073 kb)

Supplementary Figure S4

Characterization of TSA/DAC-promoted lymphoma and leukaemia in Eµ-N-Ras transgenic mice. (PDF 16142 kb)

Supplementary Table S1

Clinical and pathological characteristics of terminal disease conditions in Eµ-N-Ras mice of the indicated genotypes grouped according to their time-to-death. (PDF 156 kb)

Supplementary Table S2

Comprehensive summary of haematological differentiation measured in nucleated cell populations isolated from the indicated compartments of Suv39h1+/+ and Suv39h1-/- mice. (PDF 109 kb)

Supplementary Table S3

Chromosomal aberrations of individual primary control (n = 2), Suv39h1-null (n = 4), and p53-null Ras-lymphomas (n = 3) assessed by spectral karyotyping. (PDF 110 kb)

Supplementary Notes

Legends for Figures S1-S4 and Tables S1-S3 (DOC 25 kb)

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Braig, M., Lee, S., Loddenkemper, C. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005). https://doi.org/10.1038/nature03841

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