Résumé
In this work, Björn Lamprecht
et al
. found that survival of Hodgkin's lymphoma cells requires activity of the growth factor receptor CSF1R. Transcription of the gene encoding CSF1R was unexpectedly discovered to originate in a specific class of long terminal repeat, a type of repetitive element present in the genome. Transcriptional initiation from this class of long terminal repeats was widely activated in Hodgkin's lymphoma cells, which the authors traced to defects in epigenetic silencing (
517–518
).
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.