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Onco-exaptation of an endogenous retroviral LTR drives IRF5 expression in Hodgkin lymphoma

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Abstract

The transcription factor interferon regulatory factor 5 (IRF5) is upregulated in Hodgkin lymphoma (HL) and is a key regulator of the aberrant transcriptome characteristic of this disease. Here we show that IRF5 upregulation in HL is driven by transcriptional activation of a normally dormant endogenous retroviral LOR1a long terminal repeat (LTR) upstream of IRF5. Specifically, through screening of RNA-sequencing libraries, we detected LTR-IRF5 chimeric transcripts in multiple HL cell lines but not in normal B-cell controls. In HL, the LTR was in an open and hypomethylated epigenetic state, and we further show the LTR is the site of transcriptional initiation. Among HL cell lines, usage of the LTR promoter strongly correlates with overall levels of IRF5 mRNA and protein, indicating that LTR transcriptional awakening is a major contributor to IRF5 upregulation in HL. Taken together, oncogenic IRF5 overexpression in HL is the result of a specific LTR transcriptional activation. We propose that such LTR derepression is a distinct mechanism of oncogene activation (‘onco-exaptation’), and that such a mechanism warrants further investigation in molecular and cancer research.

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Acknowledgements

This work was supported by a grant from the Leukemia and Lymphoma Society of Canada to DM and CS, with core support provided by the British Columbia Cancer Agency. AB is supported by a studentship award from the Natural Sciences and Engineering Research Council of Canada, MMK is supported by a postdoctoral fellowship from the Michael Smith Foundation for Health Research (MSFHR) and CS is supported by a scholarship award from MSFHR.

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Correspondence to C Steidl or D L Mager.

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Babaian, A., Romanish, M., Gagnier, L. et al. Onco-exaptation of an endogenous retroviral LTR drives IRF5 expression in Hodgkin lymphoma. Oncogene 35, 2542–2546 (2016). https://doi.org/10.1038/onc.2015.308

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