title: 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.
authors.affiliation: [Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Lamprecht
authors.forename: Korden
authors.initials: K
authors.lastname: Walter
authors.forename: Stephan
authors.initials: S
authors.lastname: Kreher
authors.forename: Raman
authors.initials: R
authors.lastname: Kumar
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.forename: Dido
authors.initials: D
authors.lastname: Lenze
authors.forename: Karl
authors.initials: K
authors.lastname: Köchert
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Bouhlel
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.forename: Eric
authors.initials: E
authors.lastname: Soler
authors.forename: Ralph
authors.initials: R
authors.lastname: Stadhouders
authors.forename: Korinna
authors.initials: K
authors.lastname: Jöhrens
authors.forename: Kathrin D
authors.initials: KD
authors.lastname: Wurster
authors.forename: David F
authors.initials: DF
authors.lastname: Callen
authors.forename: Michael F
authors.initials: MF
authors.lastname: Harte
authors.forename: Maciej
authors.initials: M
authors.lastname: Giefing
authors.forename: Rachael
authors.initials: R
authors.lastname: Barlow
authors.forename: Harald
authors.initials: H
authors.lastname: Stein
authors.forename: Ioannis
authors.initials: I
authors.lastname: Anagnostopoulos
authors.forename: Martin
authors.initials: M
authors.lastname: Janz
authors.forename: Peter N
authors.initials: PN
authors.lastname: Cockerill
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Constanze
authors.initials: C
authors.lastname: Bonifer
authors.forename: Stephan
authors.initials: S
authors.lastname: Mathas
mesh_terms: D003115:Colony-Stimulating Factors / Q000235:genetics*; D015870:Gene Expression; D006689:Hodgkin Disease / Q000235:genetics; D006801:Humans; D008223:Lymphoma / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020079:Terminal Repeat Sequences; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C115744:CBFA2T3 protein, human; D003115:Colony-Stimulating Factors; C000715470:MAS1 protein, human; D010750:Phosphoproteins; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D016173:Macrophage Colony-Stimulating Factor