Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Deletion of Irf5 protects hematopoietic stem cells from DNA damage-induced apoptosis and suppresses γ-irradiation-induced thymic lymphomagenesis

Oncogene volume 33, pages 3288–3297 (2014)Cite this article

Subjects

Abstract

Repeated low-dose γ-irradiation (IR) induces thymic lymphoma in mice because of oncogenic mutations propagating from a primitive hematopoietic stem/progenitor cell (HSC) in the bone marrow. It is well known that IR-induced thymic lymphomagenesis is markedly enhanced by p53 deficiency, yet data also indicate that p53-dependent apoptosis can actively drive tumor formation in this model. The latter was recently expounded on by findings from Puma-deficient mice, indicating that loss of this proapoptotic p53 target gene results in protection from IR-induced lymphomagenesis rather than enhanced susceptibility to. Similar to Puma, the transcription factor interferon regulatory factor 5 (Irf5) has been reported as a p53 target gene and is required for DNA damage-induced apoptosis. To date, no studies have been performed to elucidate the in vivo role of IRF5 in tumorigenesis. Given its essential role in DNA damage-induced apoptosis, we explored the tumor suppressor function of IRF5 in IR-induced thymic lymphomagenesis. Somewhat surprisingly, we found that thymic lymphoma development was significantly suppressed in Irf5−/− mice as compared with wild-type littermates. Suppression was due, in part, to reduced thymocyte and HSC apoptosis, resulting in reduced compensatory proliferation, and reduced replication stress-associated DNA damage. The observed effects were independent of p53 or Puma as these proteins were upregulated in Irf5−/− mice in response to IR. This study demonstrates an important new role for IRF5 in maintaining HSC homeostasis after IR and supports the non-redundant functions of IRF5, p53 and PUMA in DNA damage-induced lymphomagenesis. We propose that IRF5 may be an attractive target for developing therapeutic agents to ameliorate radiation-induced bone marrow injury.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Rossi DJ, Jamieson CH, Weissman IL . Stem cells and the pathways to aging and cancer. Cell 2008; 132: 681–696.

    Article  CAS  Google Scholar 

  2. Elledge SJ . Cell cycle checkpoints: preventing an identity crisis. Science 1996; 274: 1664–1672.

    Article  CAS  Google Scholar 

  3. Vousden KH, Lane DP . P53 in health and disease. Nat Rev Mol Cell Biol 2007; 8: 275–283.

    Article  CAS  Google Scholar 

  4. Erlacher M, Labi V, Manzl C, Bock G, Tzankov A, Hacker G et al. Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction. J Exp Med 2006; 203: 2939–2951.

    Article  CAS  Google Scholar 

  5. Michalak EM, Villunger A, Adam JM, Strasser A . In several cell types the tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death Differ 2008; 15: 1019–1029.

    Article  CAS  Google Scholar 

  6. Kemp CJ, Wheldon T, Balmain A . P53-deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nat Genet 1994; 8: 66–69.

    Article  CAS  Google Scholar 

  7. Kelly PN, White MJ, Goschnick MW, Fairfax KA, Tarlinton DM, Kinkel SA et al. Individual and overlapping roles of BH3-only proteins Bim and Bad in apoptosis of lymphocytes and platelets and in suppression of thymic lymphoma development. Cell Death Differ 2010; 17: 1655–1664.

    Article  CAS  Google Scholar 

  8. Michalak EM, Vandenberg CJ, Delbridge ARD, Wu L, Scott CL, Adams JM et al. Apoptosis-promoted tumorigenesis: γ-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death. Genes Dev 2010; 24: 1608–1613.

    Article  CAS  Google Scholar 

  9. Labi V, Erlacher M, Krumschnabel G, Manzl C, Tzankov A, Pinon J et al. Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation. Genes Dev 2010; 24: 1602–1607.

    Article  CAS  Google Scholar 

  10. Mori T, Anazawa Y, Iiizumi M, Fukuda S, Nakamura Y, Arakawa H . Identification of the interferon regulatory factor 5 gene (IRF-5) as a direct target for p53. Oncogene 2002; 21: 2914–2918.

    Article  CAS  Google Scholar 

  11. Barnes BJ, Kellum MJ, Pinder KE, Frisancho JA, Pitha PM . Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Res 2003; 63: 6424–6431.

    CAS  Google Scholar 

  12. Hu G, Mancl ME, Barnes BJ . Signaling through IFN regulatory factor-5 sensitizes p53-deficient tumors to DNA damage-induced apoptosis and cell death. Cancer Res 2005; 65: 7403–7412.

    Article  CAS  Google Scholar 

  13. Yanai H, Chen HM, Inuzuka T, Kondo S, Mak TW, Takaoka A et al. Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression. Proc Natl Acad Sci USA 2007; 104: 3402–3407.

    Article  CAS  Google Scholar 

  14. Stankovic T, Hubank M, Cronin D, Stewart GS, Fletcher D, Bignell CR et al. Microarray analysis reveals that TP53- and ATM-mutant B-CLLs share a defect in activating proapoptotic responses after DNA damage but are distinguished by major differences in activating prosurvival responses. Blood 2004; 103: 291–300.

    Article  CAS  Google Scholar 

  15. Yang L, Zhao T, Shi X, Nakhaei P, Wang Y, Sun Q et al. Functional analysis of a dominant negative mutation of interferon regulatory factor 5. PLoS One 2009; 4: e5500.

    Article  Google Scholar 

  16. Barnes BJ, Moore PA, Pitha PM . Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. J Biol Chem 2001; 276: 23382–23390.

    Article  CAS  Google Scholar 

  17. Watkins AJ, Hamoudi RA, Zeng N, Yan Q, Huang Y, Liu H et al. An integrated genomic and expression analysis of 7q deletion in splenic marginal zone lymphoma. PLoS One 2012; 7: e44997.

    Article  CAS  Google Scholar 

  18. Fresquet V, Robles EF, Parker A, Martinez-Useros J, Mena M, Malumbres R et al. High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumor supressor in splenic marginal-zone lymphoma. Br J Haematol 2012; 158: 712–726.

    Article  CAS  Google Scholar 

  19. Kaplan HS, Brown MB . A quantitative dose–response study of lymphoid-tumor development in irradiated C57 black mice. J Natl Cancer Inst 1952; 13: 185–208.

    CAS  Google Scholar 

  20. Kaplan HS . The role of irradiation on experimental leukemogenesis. Natl Cancer Inst Monogr 1964; 14: 207–220.

    CAS  Google Scholar 

  21. Yang L, Feng D, Bi X, Stone RC, Barnes BJ . Monocytes from Irf5−/−mice have an intrinsic defect in their response to pristane-induced lupus. J Immunol 2012; 189: 3741–3750.

    Article  CAS  Google Scholar 

  22. Kim HJ, Alonzo ES, Dorothee G, Pollard JW, Snat-Angelo DB . Selective depletion of eosinophils or neutrophils in mice impacts the efficiency of apoptotic cell clearance in the thymus. PLoS One 2010; 5: e11439.

    Article  Google Scholar 

  23. Kominami R, Niwa O . Radiation carcinogenesis in mouse thymic lymphomas. Cancer Sci 2006; 97: 575–581.

    Article  CAS  Google Scholar 

  24. Bi X, Hameed M, Mirani N, Pimenta EM, Anari J, Barnes BJ . Loss of interferon regulatory factor 5 (IRF5) expression in human ductal carcinoma correlates with disease stage and contributes to metastasis. Breast Cancer Res 2011; 13: R111.

    Article  CAS  Google Scholar 

  25. Xu D, Meyer F, Ehlers E, Balsnitz L, Zhang L . Interferon regulatory factor 4 (IRF-4) targets IRF-5 to regulate Epstein–Barr virus transformation. J Biol Chem 2011; 286: 18261–18267.

    Article  CAS  Google Scholar 

  26. Hu G, Barnes BJ . IRF-5 is a mediator of the death receptor-induced apoptotic signaling pathway. J Biol Chem 2009; 284: 2767–2777.

    Article  CAS  Google Scholar 

  27. Botcheva K, McCorkle SR, McCombie WR, Dunn JJ, Anderson CW . Distinct p53 genomic binding patterns in normal and cancer-derived cell lines. Cell Cycle 2011; 10: 4237–4249.

    Article  CAS  Google Scholar 

  28. Nikulenkov F, Spinnler C, Li H, Tonnelli C, Shi Y, Turunen M et al. Insights into p53 transcriptional function via genome-wide chromatin occupancy and gene expression analysis. Cell Death Differ 2012; 19: 1992–2002.

    Article  CAS  Google Scholar 

  29. Wu WS, Heinrichs S, Xu D, Garrison SP, Zambetti GP, Adams JM et al. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 2005; 123: 641–653.

    Article  CAS  Google Scholar 

  30. Yu H, Shen H, Yuan Y, XuFeng R, Hu X, Garrison SP et al. Deletion of Puma protects hematopoietic stem cells and confers long-term survival in response to high-dose γ-irradiation. Blood 2010; 115: 3472–3480.

    Article  CAS  Google Scholar 

  31. Mauch P, Constine L, Greenberger J, Knospe W, Sullivan J, Liesveld JL et al. Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys 1995; 31: 1319–1339.

    Article  CAS  Google Scholar 

  32. Wang Y, Schulte BA, LaRue AC, Ogawa M, Zhou D . Total body irradiation selectively induces murine hematopoietic stem cell senescence. Blood 2006; 107: 358–366.

    Article  CAS  Google Scholar 

  33. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mitzutani T et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 2005; 434: 243–249.

    Article  CAS  Google Scholar 

  34. Schoenemeyer A, Barnes BJ, Mancl ME, Latz E, Goutagny N, Pitha PM et al. The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor signaling. J Biol Chem 2005; 280: 17005–17012.

    Article  CAS  Google Scholar 

  35. Feng D, Sangster-Guity N, Stone R, Korczeniewska J, Mancl ME, Fitzgerald-Bocarsly P et al. Differential requirement of histone acetylase and deacetylase activities for IRF5-mediated proinflammatory cytokine expression. J Immunol 2010; 185: 6003–6012.

    Article  CAS  Google Scholar 

  36. Feng D, Yang L, Bi X, Stone RC, Patel P, Barnes BJ . Irf5-deficient mice are protected from pristane-induced lupus via increased Th2 cytokines and altered IgG class switching. Europ J Immunol 2012; 42: 1477–1487.

    Article  CAS  Google Scholar 

  37. Liu C, Gao F, Li B, Mitchel REJ, Liu X, Lin J et al. TLR4 knockout protects mice from radiation-induced thymic lymphoma by downregulation of IL6 and miR-21. Leukemia 2011; 25: 1516–1519.

    Article  CAS  Google Scholar 

  38. Garrison SP, Jeffers JR, Yang C, Nilsson JA, Hall MA, Rehg JE et al. Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis. Mol Cell Biol 2008; 28: 5391–5402.

    Article  CAS  Google Scholar 

  39. Michalak EM, Jansen ES, Happo L, Cragg MS, Tai L, Smyth GK et al. Puma and to a lesser extent Noxa are suppressors of Myc-induced lymphomagenesis. Cell Death Differ 2009; 16: 684–696.

    Article  CAS  Google Scholar 

  40. Purtha WE, Swiecki M, Colonna M, Diamond MS, Bhattacharya D . Spontaneous mutation of the Dock2 gene in Irf5–/– mice complicates interpretation of type I interferon production and antibody responses. Proc Natl Acad Sci USA 2012; 109: E898–E904.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge Dr David Lagunoff for pathology assistance and Dr Lisong Yang for technical assistance. This work was supported in part by funds from the New Jersey Medical School-University Hospital Cancer Center, the UMDNJ Foundation and the New Jersey Commission on Cancer Research (NJCCR).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, Newark, NJ, USA

    X Bi, D Feng, J Korczeniewska & B J Barnes

  2. New Jersey Medical School-University Hospital Cancer Center, UMDNJ, Newark, NJ, USA

    X Bi, D Feng, J Korczeniewska, N Alper, G Hu & B J Barnes

Authors
  1. X Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Korczeniewska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Alper
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B J Barnes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B J Barnes.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bi, X., Feng, D., Korczeniewska, J. et al. Deletion of Irf5 protects hematopoietic stem cells from DNA damage-induced apoptosis and suppresses γ-irradiation-induced thymic lymphomagenesis. Oncogene 33, 3288–3297 (2014). https://doi.org/10.1038/onc.2013.295

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.295

Keywords

This article is cited by

Search

Advanced search

Quick links