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ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis

Oncogene volume 33, pages 129–133 (2014)Cite this article

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Abstract

Cyclin D1 deregulation is implicated in the genesis of multiple human cancers. Importantly, nuclear cyclin D1 retention during S-phase promotes DNA re-replication and subsequent genomic instability, providing a direct correlation between aberrant cyclin D1/CDK4 activity, transcriptional regulation and double strand DNA break (DSB) induction. Together, these molecular events catalyze the genomic instability necessary for neoplastic transformation. Given that replication-associated DNA damage is central to cyclin D1-driven neoplasia, inactivation of critical checkpoint mediators should augment cyclin D1-dependent tumorigenesis in vivo. To interrogate potential synergy between constitutively nuclear cyclin D1 expression and impaired DSB-induced checkpoint integrity, Ataxia Telangiectasia Mutated (ATM)-deficient mice harboring the Eμ-D1T286A transgene were generated and evaluated for tumor onset. Eμ-D1T286A/ATM−/− mice exhibit dramatically accelerated incidence of both B- and T-cell lymphomas relative to Eμ-D1T286A or ATM−/− control cohorts. Lymphomas exhibit clonal chromosomal alterations distinct from ATM−/− mice, which typically acquire translocations involving the Tcrα/δ locus during V(D)J recombination, and instead harbor alterations at the c-Myc locus. Collectively, these findings reveal an intricate relationship wherein nuclear cyclin D1/CDK4 drives genomic instability in the absence of ATM function and clonal selection of cells harboring alterations within the murine c-Myc locus, ultimately facilitating transformation and tumor formation.

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References

  1. Jares P, Campo E . Advances in the understanding of mantle cell lymphoma. Br J Haematol 2008; 142: 149–165.

    Article  CAS  PubMed  Google Scholar 

  2. Motokura T, Bloom T, Kim HG, Juppner H, Ruderman JV, Kronenberg HM et al. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 1991; 350: 512–515.

    Article  CAS  PubMed  Google Scholar 

  3. Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC . Characterization of a candidate bcl1 gene. Mol Cell Biol 1991; 11: 4846–4853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hemmer S, Wasenius VM, Haglund C, Zhu Y, Knuutila S, Franssila K et al. Deletion of 11q23 and cyclin D1 overexpression are frequent aberrations in parathyroid adenomas. Am J Pathol 2001; 158: 1355–1362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Monni O, Zhu Y, Franssila K, Oinonen R, Hoglund P, Elonen E et al. Molecular characterization of deletion at 11q22.1-23.3 in mantle cell lymphoma. Br J Haematol 1999; 104: 665–671.

    Article  CAS  PubMed  Google Scholar 

  6. Nagy B, Lundan T, Larramendy ML, Aalto Y, Zhu Y, Niini T et al. Abnormal expression of apoptosis-related genes in haematological malignancies: overexpression of MYC is poor prognostic sign in mantle cell lymphoma. Br J Haematol 2003; 120: 434–441.

    Article  CAS  PubMed  Google Scholar 

  7. Lowndes NF, Toh GW . DNA repair: the importance of phosphorylating histone H2AX. Curr Biol 2005; 15: R99–R102.

    Article  CAS  PubMed  Google Scholar 

  8. Zhou BB, Elledge SJ . The DNA damage response: putting checkpoints in perspective. Nature 2000; 408: 433–439.

    Article  CAS  PubMed  Google Scholar 

  9. Greiner TC, Dasgupta C, Ho VV, Weisenburger DD, Smith LM, Lynch JC et al. Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma. Proc Natl Acad Sci USA 2006; 103: 2352–2357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Slotta-Huspenina J, Koch I, de Leval L, Keller G, Klier M, Bink K et al. The impact of cyclin D1 mRNA isoforms, morphology and p53 in mantle cell lymphoma: p53 alterations and blastoid morphology are strong predictors of a high proliferation index. Haematologica 2012; 97: 1422–1430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Quelle DE, Ashmun RA, Shurtleff SA, Kato JY, Bar-Sagi D, Roussel MF et al. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev 1993; 7: 1559–1571.

    Article  CAS  PubMed  Google Scholar 

  12. Gladden AB, Woolery R, Aggarwal P, Wasik MA, Diehl JA . Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma. Oncogene 2006; 25: 998–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alt JR, Cleveland JL, Hannink M, Diehl JA . Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev 2000; 14: 3102–3114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Diehl JA, Zindy F, Sherr CJ . Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev 1997; 11: 957–972.

    Article  CAS  PubMed  Google Scholar 

  15. Diehl JA, Cheng M, Roussel MF, Sherr CJ . Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998; 12: 3499–3511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lin DI, Lessie MD, Gladden AB, Bassing CH, Wagner KU, Diehl JA . Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis. Oncogene 2007; 27: 1231–1242.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Aggarwal P, Lessie MD, Lin DI, Pontano L, Gladden AB, Nuskey B et al. Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication. Genes Dev 2007; 21: 2908–2922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C et al. Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. Embo J 2006; 25: 1126–1136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jin J, Arias EE, Chen J, Harper JW, Walter JC . A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell 2006; 23: 709–721.

    Article  CAS  PubMed  Google Scholar 

  20. Maiorano D, Moreau J, Mechali M . XCDT1 is required for the assembly of pre-replicative complexes in Xenopus laevis. Nature 2000; 404: 622–625.

    Article  CAS  PubMed  Google Scholar 

  21. Nishitani H, Lygerou Z, Nishimoto T, Nurse P . The Cdt1 protein is required to license DNA for replication in fission yeast. Nature 2000; 404: 625–628.

    Article  CAS  PubMed  Google Scholar 

  22. Pontano LL, Aggarwal P, Barbash O, Brown EJ, Bassing CH, Diehl JA . Genotoxic stress-induced cyclin D1 phosphorylation and proteolysis are required for genomic stability. Mol Cell Biol 2008; 28: 7245–7258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D . Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 1996; 10: 2411–2422.

    Article  CAS  PubMed  Google Scholar 

  24. Liyanage M, Weaver Z, Barlow C, Coleman A, Pankratz DG, Anderson S et al. Abnormal rearrangement within the alpha/delta T-cell receptor locus in lymphomas from Atm-deficient mice. Blood 2000; 96: 1940–1946.

    CAS  PubMed  Google Scholar 

  25. Zha S, Bassing CH, Sanda T, Brush JW, Patel H, Goff PH et al. ATM-deficient thymic lymphoma is associated with aberrant tcrd rearrangement and gene amplification. J Exp Med 2010; 207: 1369–1380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Aggarwal P, Vaites LP, Kim JK, Mellert H, Gurung B, Nakagawa H et al. Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase. Cancer Cell 2010; 18: 329–340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Serrano M, Gomez-Lahoz E, DePinho RA, Beach D, Bar-Sagi D . Inhibition of ras-induced proliferation and cellular transformation by p16INK4. Science 1995; 267: 249–252.

    Article  CAS  PubMed  Google Scholar 

  28. Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW . Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 1998; 12: 3008–3019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Walker DR, Bond JP, Tarone RE, Harris CC, Makalowski W, Boguski MS et al. Evolutionary conservation and somatic mutation hotspot maps of p53: correlation with p53 protein structural and functional features. Oncogene 1999; 18: 211–218.

    Article  CAS  PubMed  Google Scholar 

  30. Hakim O, Resch W, Yamane A, Klein I, Kieffer-Kwon KR, Jankovic M et al. DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes. Nature 2012; 484: 69–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Gostissa M, Yan CT, Bianco JM, Cogne M, Pinaud E, Alt FW . Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region. Nature 2009; 462: 803–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ramiro AR, Jankovic M, Callen E, Difilippantonio S, Chen HT, McBride KM et al. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 2006; 440: 105–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Robbiani DF, Bothmer A, Callen E, Reina-San-Martin B, Dorsett Y, Difilippantonio S et al. AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations. Cell 2008; 135: 1028–1038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ghosh M, Kemp M, Liu G, Ritzi M, Schepers A, Leffak M . Differential binding of replication proteins across the human c-myc replicator. Mol Cell Biol 2006; 26: 5270–5283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Girard-Reydet C, Gregoire D, Vassetzky Y, Mechali MDNA . replication initiates at domains overlapping with nuclear matrix attachment regions in the xenopus and mouse c-myc promoter. Gene 2004; 332: 129–138.

    Article  CAS  PubMed  Google Scholar 

  36. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T . Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 2000; 102: 553–563.

    Article  CAS  PubMed  Google Scholar 

  37. Zhou J, Ashouian N, Delepine M, Matsuda F, Chevillard C, Riblet R et al. The origin of a developmentally regulated Igh replicon is located near the border of regulatory domains for Igh replication and expression. Proc Natl Acad Sci USA 2002; 99: 13693–13698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Norio P, Kosiyatrakul S, Yang Q, Guan Z, Brown NM, Thomas S et al. Progressive activation of DNA replication initiation in large domains of the immunoglobulin heavy chain locus during B cell development. Mol Cell 2005; 20: 575–587.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Margarita Romero for excellent technical assistance and maintenance of the mouse colony, Dr Eric Brown for providing ATM+/− mice for colony generation and insightful comments on the work, the AFCRI histology core for assistance with tissue paraffin embedding and sectioning, and Dr Priya Aggarwal for assistance with flow cytometry and cytogenetic techniques. This work was supported by a grant from the NIH (CA93237) (JAD).

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Authors and Affiliations

  1. The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA

    L P Vaites, Z Lian, E K Lee & J A Diehl

  2. Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA

    L P Vaites, Z Lian, E K Lee & J A Diehl

  3. Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    B Yin, A DeMicco & C H Bassing

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  1. L P Vaites
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  2. Z Lian
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Correspondence to J A Diehl.

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Vaites, L., Lian, Z., Lee, E. et al. ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis. Oncogene 33, 129–133 (2014). https://doi.org/10.1038/onc.2012.577

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  • DOI: https://doi.org/10.1038/onc.2012.577

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