Skip to main content

Thank you for visiting 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.

Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma


Mammalian genomes contain many repetitive elements, including long terminal repeats (LTRs), which have long been suspected to have a role in tumorigenesis. Here we present evidence that aberrant LTR activation contributes to lineage-inappropriate gene expression in transformed human cells and that such gene expression is central for tumor cell survival. We show that B cell–derived Hodgkin's lymphoma cells depend on the activity of the non-B, myeloid-specific proto-oncogene colony-stimulating factor 1 receptor (CSF1R). In these cells, CSF1R transcription initiates at an aberrantly activated endogenous LTR of the MaLR family (THE1B). Derepression of the THE1 subfamily of MaLR LTRs is widespread in the genome of Hodgkin's lymphoma cells and is associated with impaired epigenetic control due to loss of expression of the corepressor CBFA2T3. Furthermore, we detect LTR-driven CSF1R transcripts in anaplastic large cell lymphoma, in which CSF1R is known to be expressed aberrantly. We conclude that LTR derepression is involved in the pathogenesis of human lymphomas, a finding that might have diagnostic, prognostic and therapeutic implications.

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

Access options

Rent or buy this article

Prices vary by article type



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

Figure 1: Lineage-inappropriate expression of CSF1R is required for survival of Hodgkin's lymphoma cells.
Figure 2: HRS cells express CSF1R from a different promoter than do myeloid cells.
Figure 3: The noncanonical CSF1R transcript in HRS cells initiates at an aberrantly activated LTR.
Figure 4: Analysis of CSF1R LTR DNA methylation and CBFA2T3 expression.
Figure 5: CBFA2T3 expression is lacking in primary HRS cells, full CSF1R LTR activation requires CBFA2T3 downregulation and active NF-κB and THE1 activation occurs in HRS cells at many genomic locations.
Figure 6: LTR-CSF1R transcripts are expressed in anaplastic large cell lymphoma (ALCL) specimens.

Accession codes


Gene Expression Omnibus


  1. Jern, P. & Coffin, J.M. Effects of retroviruses on host genome function. Annu. Rev. Genet. 42, 709–732 (2008).

    Article  CAS  Google Scholar 

  2. Smit, A.F. Identification of a new, abundant superfamily of mammalian LTR-transposons. Nucleic Acids Res. 21, 1863–1872 (1993).

    Article  CAS  Google Scholar 

  3. Maksakova, I.A., Mager, D.L. & Reiss, D. Keeping active endogenous retroviral-like elements in check: the epigenetic perspective. Cell. Mol. Life Sci. 65, 3329–3347 (2008).

    Article  CAS  Google Scholar 

  4. Faulkner, G.J. et al. The regulated retrotransposon transcriptome of mammalian cells. Nat. Genet. 41, 563–571 (2009).

    Article  CAS  Google Scholar 

  5. Druker, R. & Whitelaw, E. Retrotransposon-derived elements in the mammalian genome: a potential source of disease. J. Inherit. Metab. Dis. 27, 319–330 (2004).

    Article  CAS  Google Scholar 

  6. Ehrlich, M. DNA methylation in cancer: too much, but also too little. Oncogene 21, 5400–5413 (2002).

    Article  CAS  Google Scholar 

  7. Fan, T. et al. DNA hypomethylation caused by Lsh deletion promotes erythroleukemia development. Epigenetics 3, 134–142 (2008).

    Article  Google Scholar 

  8. Howard, G., Eiges, R., Gaudet, F., Jaenisch, R. & Eden, A. Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene 27, 404–408 (2008).

    Article  CAS  Google Scholar 

  9. Eden, A., Gaudet, F., Waghmare, A. & Jaenisch, R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300, 455 (2003).

    Article  CAS  Google Scholar 

  10. Huang, J. et al. Lsh, an epigenetic guardian of repetitive elements. Nucleic Acids Res. 32, 5019–5028 (2004).

    Article  CAS  Google Scholar 

  11. Borowitz, M.J., Béné, M.C., Harris, N.L., Porwit, A. & Matutes, E. Acute leukaemias of ambiguous lineage. in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (eds. Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J. & Vardiman, J.W.) 149–155 (IARC, Lyon, 2008).

  12. Feldman, A.L. et al. Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone. Blood 111, 5433–5439 (2008).

    Article  CAS  Google Scholar 

  13. Küppers, R. The biology of Hodgkin′s lymphoma. Nat. Rev. Cancer 9, 15–27 (2009).

    Article  Google Scholar 

  14. Janz, M., Dörken, B. & Mathas, S. Reprogramming of B lymphoid cells in human lymphoma pathogenesis. Cell Cycle 5, 1057–1061 (2006).

    Article  CAS  Google Scholar 

  15. Küppers, R. et al. Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling. J. Clin. Invest. 111, 529–537 (2003).

    Article  Google Scholar 

  16. Mathas, S. et al. Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma. Nat. Immunol. 7, 207–215 (2006).

    Article  CAS  Google Scholar 

  17. Pixley, F.J. & Stanley, E.R. CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol. 14, 628–638 (2004).

    Article  CAS  Google Scholar 

  18. Moreau, A., Praloran, V., Berrada, L., Coupey, L. & Gaillard, F. Immunohistochemical detection of cells positive for colony-stimulating factor 1 in lymph nodes from reactive lymphadenitis, and Hodgkin′s disease. Leukemia 6, 126–130 (1992).

    CAS  PubMed  Google Scholar 

  19. Irvine, K.M. et al. A CSF-1 receptor kinase inhibitor targets effector functions and inhibits pro-inflammatory cytokine production from murine macrophage populations. FASEB J. 20, 1921–1923 (2006).

    Article  CAS  Google Scholar 

  20. Burns, C.J. et al. Discovery of 2-(α-methylbenzylamino) pyrazines as potent Type II inhibitors of FMS. Bioorg. Med. Chem. Lett. 19, 1206–1209 (2009).

    Article  CAS  Google Scholar 

  21. Bonifer, C. & Hume, D.A. The transcriptional regulation of the colony-stimulating factor 1 receptor (CSF1R) gene during hematopoiesis. Front. Biosci. 13, 549–560 (2008).

    Article  CAS  Google Scholar 

  22. Jundt, F. et al. Loss of PU.1 expression is associated with defective immunoglobulin transcription in Hodgkin and Reed-Sternberg cells of classical Hodgkin disease. Blood 99, 3060–3062 (2002).

    Article  CAS  Google Scholar 

  23. Follows, G.A., Tagoh, H., Lefevre, P., Morgan, G.J. & Bonifer, C. Differential transcription factor occupancy but evolutionarily conserved chromatin features at the human and mouse M-CSF (CSF-1) receptor loci. Nucleic Acids Res. 31, 5805–5816 (2003).

    Article  CAS  Google Scholar 

  24. Visvader, J. & Verma, I.M. Differential transcription of exon 1 of the human c-fms gene in placental trophoblasts and monocytes. Mol. Cell. Biol. 9, 1336–1341 (1989).

    Article  CAS  Google Scholar 

  25. Hug, B.A. & Lazar, M.A. ETO interacting proteins. Oncogene 23, 4270–4274 (2004).

    Article  CAS  Google Scholar 

  26. Joos, S. et al. Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. Blood 99, 1381–1387 (2002).

    Article  CAS  Google Scholar 

  27. Ohshima, K. et al. Chromosome 16q deletion and loss of E-cadherin expression in Hodgkin and Reed-Sternberg cells. Int. J. Cancer 92, 678–682 (2001).

    Article  CAS  Google Scholar 

  28. Delhase, M., Hayakawa, M., Chen, Y. & Karin, M. Positive and negative regulation of IκB kinase activity through IKKβ subunit phosphorylation. Science 284, 309–313 (1999).

    Article  CAS  Google Scholar 

  29. Mathas, S. et al. Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma. Proc. Natl. Acad. Sci. USA 106, 5831–5836 (2009).

    Article  CAS  Google Scholar 

  30. Kacinski, B.M. CSF-1 and its receptor in ovarian, endometrial and breast cancer. Ann. Med. 27, 79–85 (1995).

    Article  CAS  Google Scholar 

  31. Chambers, S.K., Kacinski, B.M., Ivins, C.M. & Carcangiu, M.L. Overexpression of epithelial macrophage colony-stimulating factor (CSF-1) and CSF-1 receptor: a poor prognostic factor in epithelial ovarian cancer, contrasted with a protective effect of stromal CSF-1. Clin. Cancer Res. 3, 999–1007 (1997).

    CAS  PubMed  Google Scholar 

  32. Kluger, H.M. et al. Macrophage colony-stimulating factor-1 receptor expression is associated with poor outcome in breast cancer by large cohort tissue microarray analysis. Clin. Cancer Res. 10, 173–177 (2004).

    Article  CAS  Google Scholar 

  33. Gamou, T. et al. The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8(ETO) family. Blood 91, 4028–4037 (1998).

    CAS  PubMed  Google Scholar 

  34. Ehlers, A. et al. Histone acetylation and DNA demethylation of B cells result in a Hodgkin-like phenotype. Leukemia 22, 835–841 (2008).

    Article  CAS  Google Scholar 

  35. Chyla, B.J. et al. Deletion of Mtg16, a target of t(16;21), alters hematopoietic progenitor cell proliferation and lineage allocation. Mol. Cell. Biol. 28, 6234–6247 (2008).

    Article  CAS  Google Scholar 

  36. Mathas, S. et al. Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-κB. EMBO J. 21, 4104–4113 (2002).

    Article  CAS  Google Scholar 

  37. Goardon, N. et al. ETO2 coordinates cellular proliferation and differentiation during erythropoiesis. EMBO J. 25, 357–366 (2006).

    Article  CAS  Google Scholar 

  38. Walter, K., Bonifer, C. & Tagoh, H. Stem cell-specific epigenetic priming and B cell-specific transcriptional activation at the mouse Cd19 locus. Blood 112, 1673–1682 (2008).

    Article  CAS  Google Scholar 

  39. Kumar, R. et al. CBFA2T3–ZNF652 corepressor complex regulates transcription of the E-box gene HEB. J. Biol. Chem. 283, 19026–19038 (2008).

    Article  CAS  Google Scholar 

Download references


We thank F. Hummel, S. Kressmann, S. Meier, C. Cieluch, B. Wollert-Wulf and R. Zühlke-Jenisch for outstanding technical assistance, H. Tagoh for help with experiments, P. Rahn for cell sorting and K. Rajewsky for helpful discussion and critical reading of the manuscript. M.G. is funded by the Federation of European Biochemical Societies. This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (SFB/TRR54), the Wilhelm Sander-Stiftung, the Deutsche Krebshilfe, the KinderKrebsInitiative Buchholz/Holm-Seppensen, Susan G. Komen for the Cure, Leukaemia and Lymphoma Research, Cancer Research UK and Yorkshire Cancer Research. We also thank V. Diehl (University Cologne) for cell lines L1236 and L591, A. Engert (University Cologne) for L540Cy cells, P. Krammer (German Cancer Research Center Heidelberg) for BJAB cells, L. Staudt (US National Cancer Institute) for OCI-Ly3 and OCI-Ly10 cells, M. Falk (Helmholtz Zentrum München) for BL-60 cells and S. Rosen (Northwestern University) for MM1.S cells.

Author information

Authors and Affiliations



B.L., K.W. and S.K. designed and performed experiments, interpreted data and contributed to writing of the manuscript; D.F.C., R.K., D.L. and M.F.H. gave technical support and contributed material; M.H., K.J., H.S. and I.A. performed and interpreted IHC and ISH analyses; J.R., M.G. and R. Siebert designed, performed and interpreted bisulfite pyrosequencing and FICTION analyses; M.A.B., K.D.W., R.B., E.S. and R. Stadhouders performed experiments; P.N.C. designed TD-PCR experiments and interpreted data; K.K. analyzed microarray data and performed real-time PCR analyses; M.J. and B.D. interpreted data and contributed to the writing of the manuscript; C.B. and S.M. designed research, interpreted data, wrote the manuscript and supervised the project.

Corresponding authors

Correspondence to Constanze Bonifer or Stephan Mathas.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12, Supplementary Tables 1–5 and Supplementary Methods (PDF 4469 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lamprecht, B., Walter, K., Kreher, S. et al. Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nat Med 16, 571–579 (2010).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing