Editors' ChoiceCancer

Taking Out the Trash

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Science Translational Medicine  12 May 2010:
Vol. 2, Issue 31, pp. 31ec74
DOI: 10.1126/scitranslmed.3001252

Many kinds of repetitive DNA sequences reside in mammalian genomes, including long-terminal repeats (LTRs), which house transcriptional regulatory elements such as promoters that drive the transcription of adjacent genes. These promoters are silenced under normal conditions by DNA methylation. But there are many examples of human RNA transcripts that are initiated within LTRs, suggesting that under certain conditions the promoter elements are derepressed and activate transcription.

Now, Lamprecht et al. have identified a LTR whose derepression promotes lineage-inappropriate expression of downstream genes that are important for the survival of a common lymphoid neoplasm, Hodgkin’s lymphoma. Specifically, Lamprecht et al. showed that the promoter of the THE1B LTR is aberrantly activated in Hodgkin’s lymphoma cell lines and patient samples but not in most non-Hodgkin’s lymphomas. This activation arises from demethylation of the THE1B LTR promoter and DNA methylation–induced silencing of the gene that encodes the THE1B LTR transcriptional repressor CBFA2T3. Activation of the THE1B LTR promoter and transcription factors such as NF-κB leads to the up-regulation of transcription of the colony-stimulating factor 1 receptor gene (CSF1R), which lives downstream of the THE1B LTR and is not normally expressed in B cells. Enhanced CSF1R expression in turn promotes proliferation of Hodgkin’s lymphoma cells.

The observation that aberrant activation of other LTRs of the THE1 subfamily, besides THE1B, drives the expression of other downstream transcripts in addition to CSF1R suggests that other oncogenes may be re-expressed through this same mechanism. However, it is clear that CSF1R, whose expression is restricted to Hodgkin’s lymphoma and one other lymphoma subtype called anaplastic large cell lymphoma (ALCL), is clinically relevant. A diagnostic test that quantifies the amount of CSF1R transcripts in cells or bodily fluids may permit detection of these tumors or the selection of patients for treatment with already exisiting inhibitors of CSF1R function. Lastly, CSF1R expression may be a useful marker to detect minimal residual disease in lymphoma patients who have undergone treatment.

This work highlights the importance of aberrant activation of LTR promoters in cancer formation. Repetitive DNA elements were previously considered to be nonfunctional “junk” or “trash” DNA cluttering mammalian genomes. If this work helps to identify a new way to treat Hodgkin’s lymphoma and ALCL by conquering the downstream consequences of LTR reactivation, then scientists will have found a treasure in taking out the trash.

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

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