Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

Abstract

Endogenous retroviruses (ERVs) and other transposons can act as tissue-specific regulators of gene expression in cis, with potential to affect biological processes. In cancer, epigenetic alterations and transcription factor misregulation may uncover the regulatory potential of typically repressed ERVs, which could contribute to tumour evolution and progression. Here, we asked whether transposons help to rewire oncogenic transcriptional circuits in acute myeloid leukemia (AML). Using epigenomic data from both primary cells and cell lines, we have identified six ERV families that are frequently found in an open chromatin state in AML when compared to differentiated healthy myeloid cells. A subset of these AML-associated ERVs harbour enhancerspecific histone modifications, and are bound by hematopoiesis-associated transcription factors that play key roles in haematopoiesis and in the pathogenesis of AML. Using CRISPR-mediated genetic editing and simultaneous epigenetic silencing of multiple ERV copies, we have established causal links between ERV deregulation in AML and expression changes of adjacent genes. Finally, we show that deletion and epigenetic silencing of an ERV, through modulating expression of APOC1 gene, leads to growth suppression by inducing apoptosis in leukemia cell lines. Our results suggest that ERV derepression provides an additional layer of gene regulation in AML that may be exploited by cancer cells to help drive oncogenic phenotypes. 10% or more of the AML samples ( Figure 1B). Five of these families were highly enriched across all samples, including macrophages and monocytes, as well as mobilized CD34+ cells (data from the Roadmap epigenomics project), suggesting little cell specificity. The remaining seven families displayed more variability between AML samples and, notably, tended to display little to no enrichment in differentiated myeloid cells ( Figure 1B). Nearly all families were also DHS-enriched in CD34+ cells, suggesting an association with a stem cell state. The exception was the LTR2B family, whose DHS enrichment appeared to be AML-specific. Analysis of an independent

Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis

“…Our work expands the TE expression-based perspective to a role of accessible TEs as cis-regulatory elements. Among the TE subfamilies accessible in LSCs, for example, we observed the LTR12C subfamily, whose elements work as enhancers in AML 34 and were previously shown to act as alternative promoters in hepatocellular carcinoma 71 . We further show that accessible TEs provide docking sites for oncogenic transcription regulators in LSCs.…”

Host Gene Regulation by Transposable Elements: The New, the Old and the Ugly

“…Notably, it has also been reported that infection by Epstein-Barr Virus can lead to the activation of LTRs, such as ERV1 and ERVL, in the context of primary B-cells and lymphoblastoid cell lines [ 126 ]. New examples of LTRs functioning as enhancers to disease-relevant genes have recently been discovered for acute myeloid leukaemia [ 127 ]. Cancers are not only associated with upregulation of ERV regulatory elements but also the production of exapted TE-derived proteins that regulate the immune response [ 128 ].…”

Genome-wide bioinformatic analyses predict key host and viral factors in SARS-CoV-2 pathogenesis

“…Other LTR elements are also enriched in STAT1 binding sites (MLT1L) [14], or have been shown to act as cellular gene enhancers (LTR13A [16,31]).…”