Onco-exaptation of an endogenous retroviral LTR drives IRF5 expression in Hodgkin lymphoma.
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.
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
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Babaian
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
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Romanish
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
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Gagnier
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
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Kuo
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.|Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
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Karimi
Department of Lymphoid Cancer Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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Steidl
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
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Mager
D020077:Endogenous Retroviruses / Q000235:genetics*; D019143:Evolution, Molecular; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020079:Terminal Repeat Sequences / Q000235:genetics*; D015533:Transcriptional Activation
C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D012333:RNA, Messenger