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.

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

“…Interestingly, intron 3 sequences of LAT2 were significantly enriched after ChIP with the anti-ETO antibody in Kasumi-1 cells compared with U937 cells (Figure 2b, upper panel). As control for ChIP procedure, we chose the TBP (TATA box binding protein) gene, which is known to have no bona fide AML1 consensus binding sites (Lamprecht et al, 2010). Indeed, no AML1/ETO occupancy was found as measured by real-time DNA-PCR after ChIP with anti-ETO antibody (Figure 2b, lower panel).…”

“…Immunoprecipitates (at least three independent experiments) were quantified by DNA quantitative PCR (qPCR) (primers listed in Materials and methods). As a negative control, DNA qPCRs of two regions of the TBP gene, known to have no AML1 binding sites on its promoter (Lamprecht et al, 2010), were performed (lower panel). Student's t-test was applied to test for significance.…”

A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma

“…Moreover, Hodgkin and Reed-Sternberg cells are known to express several additional markers usually expressed by antigenpresenting cells. [46][47][48] Although Hodgkin and ReedSternberg cells have usually lost their B-cell phenotype, they have maintained the features for an interaction with T cells, which is not observed in the tumor cells of ALK À anaplastic large cell lymphoma. Interestingly, Hodgkin lymphoma cases with granzyme B expression were less frequently positive for MDC/CCL22 and CD83 than conventional classical Hodgkin lymphoma cases.…”

Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

“…Thus, HRS cells express 8 RTKs, platelet-derived growth factor receptor (PDGFR) a, DDR2, EPHB1, RON, TRKA, TRKB, TIE1, and CSF1R, in varying patterns, and PDGFRa and TRKA have been shown to be activated in primary cases (5)(6)(7). As mutations affecting RTKs could not be detected in HRS cell lines and as activating ligands were frequently co-expressed in HRS cells or expressed by surrounding cells in the infiltrate of primary Hodgkin lymphoma cases (5), the receptors are presumed to be activated in an autocrine or paracrine fashion.…”