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

Abstract

Acute myeloid leukemia (AML) is characterised by a series of genetic and epigenetic alterations that result in deregulation of transcriptional networks. One understudied source of transcriptional regulators are transposable elements (TEs), whose aberrant usage could contribute to oncogenic transcriptional circuits. However, the regulatory influence of TEs and their links to AML pathogenesis remain unexplored. Here we identify six endogenous retrovirus (ERV) families with AML-associated enhancer chromatin signatures that are enriched in binding of key regulators of hematopoiesis and AML pathogenesis. Using both locus-specific genetic editing and simultaneous epigenetic silencing of multiple ERVs, we demonstrate that ERV deregulation directly alters the expression of adjacent genes in AML. Strikingly, deletion or epigenetic silencing of an ERV-derived enhancer suppresses cell growth by inducing apoptosis in leukemia cell lines. This work reveals that ERVs are a previously unappreciated source of AML enhancers that may be exploited by cancer cells to help drive tumour heterogeneity and evolution.

Endogenous retroviruses in the origins and treatment of cancer

“…These data collectively lend themselves to an extended model of KAP1 silencing in which lineage-specific KZFP expression facilitates tissue-specific ERV control and domestication [ 22 , 53 , 54 ]. KAP1-mediated repression is therefore an appealing target to precisely modulate ERV activity, especially as CRISPR-dCas9 fusion proteins have proven adept for this purpose in vitro [ 10 , 12 , 45 , 92 , 93 ].…”

“…New viral infections, ERVs, and the innate immune system, coincide in vivo. Exogenous retroviruses can drive pathogenesis directly by insertional mutagenesis or introducing new regulatory elements, and indirectly by activating ERVs [ 43 , 45 , 129 , 130 ]. A major cause of liver cirrhosis and hepatocellular carcinoma, for example, is hepatitis B virus (HBV) infection.…”

“…Firstly, any cancer therapy intended to target ERV families must consider that each of its copies, including those proximal to key cancer genes, may not behave in the same way. Secondly, as epigenetic repression may be more, or less, enforced on each ERV locus, the accessible complement of ERV regulatory elements is changed, making both tumor suppressor gene downregulation and oncogene upregulation possible at a time and place that alters the course of disease [ 43 , 45 , 127 , 143 , 144 , 152 , 153 ].…”

“…1 a) appear presently incapable of retrotransposition, despite identification of polymorphic ERV insertions and HERV-K (HML-2) family copies with intact open reading frames (ORFs) [ 30 , 31 , 34 – 41 ]. Immobile ERVs, and particularly their flanking long terminal repeats (LTRs), can nonetheless contain promoter [ 21 , 26 , 27 , 42 – 44 ] and enhancer elements [ 13 , 16 , 45 ], provide an extensive repertoire of transcription factor binding sites [ 46 – 48 ], and attract DNA and histone modifying complexes [ 49 – 54 ]. These features imbue ERVs with substantial capacity to regulate the expression of gene networks required for normal cell function.…”

Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter

“…Using genome and epigenome editing approaches in AML cell lines, the authors detected six ERV families which bore chromatin signatures of enhancers and could regulate the host gene expression. It is to be noted that the deletion of the AML-specific LTR2B elements decreased proliferation and induced the apoptosis of AML cell lines by reducing the expression of the apolipoprotein C1 ( APOC1 ), an oncogene ( 72 ).…”