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

Abstract

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.

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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.

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Acknowledgements

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.

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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.

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Correspondence to Constanze Bonifer or Stephan Mathas.

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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). https://doi.org/10.1038/nm.2129

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