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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.
deletion or epigenetic silencing of an ERV-derived enhancer suppresses cell growth by inducing apoptosis in leukemia cell lines
family-wide silencing does not isolate one enhancer, and apoptosis is demonstrated after deletion rather than CRISPRi
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
independent AML datasets support enhancer signatures, although TF-binding evidence partly relies on proxy cell systems
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
cell-line perturbations support regulation, but primary AML remains observational and clone-level statistical dependence limits locus-specific inference
the APOC1-LTR2 element is essential for proliferation of leukaemia cells by acting as an enhancer of the APOC1 gene, which in turn controls cell survival via an anti-apoptotic mechanism
cell-line deletion links the element to expression and apoptosis, but no APOC1 rescue establishes mediation
Derived from the full evaluation — not a separate score.
Strengths
Two primary-AML epigenomic datasets support the identification of six ERV families with enhancer-associated signatures, extending the analysis beyond cancer-associated LTR promoters.
↳ Introduction; Results, Figs 1–3
dCas9 occupancy and histone-mark profiling assess CRISPRi target engagement, and putative off-target peaks are included in downstream analysis.
↳ Results, Inactivation of LTR2B elements leads to growth suppression; Fig. 5
The onco-exaptation discussion separates regulatory activity from a demonstrated cancer-cell advantage and identifies primary-sample and in vivo validation as necessary next steps.
↳ Discussion
Limitations
Fig. 4 applies ordinary ANOVA or t tests to samples collected repeatedly from the same clones. The reported analysis does not account for their dependence, limiting confidence in the locus-deletion expression tests.
↳ Fig. 4b–d legend
The Fig. 4 deletion results lack rescue or an independent perturbation of each same locus. Family-wide CRISPRi supports the broader regulatory hypothesis but does not establish specificity for those individual deletions.
↳ Results, Genetic excision of A-DAR elements interferes with host gene expression; Fig. 4
CRISPRi targets many LTR2B/LTR2 copies, whereas apoptosis is directly measured after APOC1-LTR2 deletion. Without APOC1 rescue, the proposed enhancer–APOC1–survival chain remains incompletely established.
↳ Abstract; Results, APOC1-associated LTR2 section; Figs 5–6
The genomic discovery arm and selected perturbations establish ERV-derived enhancers as a substantive lead in AML regulatory biology. The main methodological constraint is Fig. 4, where repeated samples from a few clones enter ordinary significance tests and individual deletion effects lack independent same-locus validation. The APOC1 experiments add cellular evidence in two leukaemia lines, but they do not establish that APOC1 mediates the entire survival phenotype. The Discussion provides meaningful context and validation requirements, while the abstract presents a more specific mechanism than the experimental package demonstrates.
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Sound3.0
Confidence mediumThe score reflects an enhancer-focused advance beyond prior cancer-associated LTR promoter work, supported by genomic discovery and selected functional tests. Functional breadth remains restricted to a small set of loci and transformed cell systems.
Deletion, CRISPRi, and target-engagement profiling provide complementary evidence, but Fig. 4 treats longitudinal clone measurements as independent observations. Those same locus-specific claims lack independent same-locus validation, producing two distinct serious methodological failures.
The discovery-to-perturbation progression is followable, but the abstract combines family-wide silencing and single-enhancer apoptosis into a more specific causal story than the experiments establish. Assertions of APOC1-mediated survival also exceed the unrescued mechanism.
The paper engages promoter-centred TE cancer research and the onco-exaptation debate while connecting important limitations to further validation. Some statements about distinguishing support for oncogenesis remain broader than the cell-line evidence.
Caveats4 of 4 checks
The reported numbers and statistics are consistent with the stated results.
The Fig. 6c and 6d legends give reversed replicate counts at the same culture time points without explaining whether the assays used different replicate sets. This does not establish that either count is incorrect.
Data availability: declared
67 of 67 checkable references verified
67 references in manuscript 21 references confirmed by manual review
References not verified automatically are resolved manually within 24 hours.
No retraction or expression of concern found in Crossref (includes Retraction Watch).
Sources: Crossref (incl. Retraction Watch) ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
Genetic and epigenetic perturbations provide laboratory evidence of regulatory and cellular effects, not an actionable intervention. Primary-AML dependency and in vivo validation remain necessary.
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