3 Minutes
Background: from "junk" sequences to therapeutic targets
Nearly half of the human genome is made up of repetitive sequences called transposable elements (TEs). Historically labeled "junk DNA," these sequences can move or copy themselves across the genome. New research from King’s College London shows that in blood cancers with mutations in regulatory genes ASXL1 and EZH2, TEs become abnormally active. That activation creates DNA damage and biochemical stress that cancer cells must manage to survive.
The study: how mutations expose a weakness
The team studied two hard-to-treat blood malignancies: myelodysplastic syndrome (MDS) and chronic lymphocytic leukemia (CLL). Both frequently carry loss-of-function mutations in ASXL1 and EZH2, genes that normally repress inappropriate gene activity through chromatin regulation. When those brakes fail, TEs are derepressed and their movement or transcription increases, producing DNA breaks and other lesions.
Experimental validation
To test whether TE activity creates a therapeutic vulnerability, researchers combined pharmacological tools and genetic assays. They observed that blocking poly (ADP-ribose) polymerase (PARP) proteins — key factors in single-strand DNA repair — selectively killed cancer cells with high TE activity. Crucially, adding reverse transcriptase inhibitors (which prevent TE copying) reversed this sensitivity, demonstrating that PARP inhibitors were effective because of TE-induced DNA damage rather than canonical BRCA-related repair defects.
Repurposing PARP inhibitors: a new mechanism
PARP inhibitors are already approved for treating tumors with homologous recombination defects (for example, BRCA-mutant cancers). This study reveals an alternative mechanism: in ASXL1- or EZH2-mutant cells, active transposable elements generate DNA lesions that depend on PARP-mediated repair. Inhibiting PARP therefore permits damage to accumulate until cancer cells die — a synthetic lethal interaction driven by "junk DNA."
Clinical implications and future prospects
Because PARP inhibitors are clinically available, this discovery could accelerate new treatment strategies for patients with MDS and CLL who harbor ASXL1 or EZH2 mutations. The approach could also be relevant to other cancers where chromatin regulators are mutated and TEs are derepressed. Future directions include biomarker development (TE expression or mutation profiling) and clinical trials testing PARP inhibitors alone or combined with agents that modulate TE activity.
Professor Chi Wai Eric So of King’s College London summarized the significance: the work reframes sequences once dismissed as nonfunctional into a practical therapeutic vulnerability, enabling existing drugs to be repurposed in a novel way.
Conclusion
This research turns attention to a previously overlooked genomic component — transposable elements — and shows how their misregulation in ASXL1- and EZH2-mutant blood cancers creates a targetable weakness. By exploiting TE-driven DNA damage with PARP inhibitors, scientists have identified a promising route to treat otherwise hard-to-target malignancies. Ongoing translational work will determine which patients benefit most and how best to integrate this strategy into clinical care.
Source: scitechdaily
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