TE-PARPi as a precision weapon against hematologic cancers Free

In this issue of Blood, Zeisig et al¹ reveal that loss-of-function mutations in the epigenetic regulators ASXL1 and EZH2 drive blood cancers by reactivating transposable elements (TEs), which induce DNA damage and create a vulnerability to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors (PARPis). Unlike traditional PARPi sensitivity tied to defective DNA repair (BRCAness), this new mechanism depends on TE activity and can be reversed with reverse transcriptase inhibitors, offering a novel therapeutic approach for these hard-to-treat cancers.

TEs, once thought of as junk DNA, are jumping genes. They are classified into 2 major classes based on their transposition mechanisms, namely, class 1 retrotransposons, which move via an RNA intermediate through a copy-and-paste mechanism, and class 2 DNA transposons, which move via a DNA intermediate. Retrotransposons include long terminal repeat (LTR) elements, which use integrase for integration, and non-LTR elements, like long interspersed elements (LINEs) and short interspersed elements (SINEs), which use target-primed reverse transcription. DNA transposons move by cut-and-paste or, in the case of Helitrons, a peel-and-paste method that involves circular DNA.

TEs can disrupt gene function and genome stability if left unchecked, so organisms have evolved complex systems to silence them. TE expression is controlled mainly by epigenetic mechanisms. These include DNA methylation, histone modifications, and RNA interference pathways, particularly the Piwi-interacting RNA (piRNA) pathway in animals.² By repressing TEs, cells maintain genomic integrity and protect against mutations that could lead to diseases like cancer or infertility. Polycomb repressive complexes (PRCs) are key epigenetic regulators that are involved in gene silencing, and they also play an important role in repressing TEs. There are 2 main types, namely, PRC1 and PRC2. PRC2 adds methyl groups to histone H3 at lysine 27 (H3K27me3), a mark associated with silenced chromatin, whereas PRC1 recognizes this mark and helps compact the chromatin to maintain repression. In the context of TEs, PRCs help their silencing by modifying the chromatin structure around them, thereby preventing their transcription.³ This is especially important in early development and in stem cells in which genome integrity is critical. Although TEs are more commonly associated with other silencing mechanisms like DNA methylation and piRNAs, PRCs provide an additional layer of control, particularly for endogenous retroviruses and other TEs that may escape traditional silencing pathways.

Although TEs are normally silenced, there are many cases in which they are activated, for example, during development.^4,5 Reactivated TEs can produce viral mimicry and activate RNA and DNA sensors (through reverse transcription), and this leads to the activation of an interferon response. In the hematopoietic system, chemotherapy⁶ was shown to lead to viral mimicry in hematopoietic stem cells but also stress hematopoiesis during pregnancy.⁷ TEs can also induce mutations through novel genome insertions or regulate transcription by populating and controlling regulatory regions like enhancers.⁸ In hematopoiesis, PARPis are a class of drugs that block the activity of PARP enzymes, which are involved in DNA repair, particularly in the repair of single-strand breaks. Recent research has shown that PARP inhibition can have indirect effects on TEs, especially in cancer cells. For example, inhibition of EHMT1/2 resensitizes cells to PARPi in ovarian cancer.⁹ 

In the study by Zeisig et al, the authors investigated how loss-of-function mutations in 2 Polycomb group epigenetic regulators, EZH2 and ASXL1, contribute to blood cancers and create a unique vulnerability to PARPi. These mutations, commonly seen in hematologic malignancies, lead to reactivation of TEs and increased DNA-damage responses. Using genetically engineered mouse models and patient-derived samples, the researchers found that Asxl1/Ezh2 double-mutant cells, but not single-mutant cells, show high sensitivity to PARPi, which induces lethal DNA damage. Interestingly, this effect depends on TE activity and not on traditional deficient homologous recombination. They demonstrated that reverse transcriptase inhibitors, which block TE replication, can rescue the cells from PARPi-induced death (see panel). Epigenetic disruption that leads to TE reactivation, whether via DNA methylation loss, impaired histone silencing, or Polycomb group mutations, can create immunogenic and genomic stresses that sensitize tumors to DNA-damage agents like PARPi. However, epigenetic TE reactivation does not always equate to therapeutic vulnerability, and PARPi resistance remains a challenge, even with epigenetic co-therapy. Multiple clinical trials that combined PARPi with epigenetic modifiers (eg, DNA methyltransferase inhibitor + PARPi) have yielded negative results in solid tumors, especially in BRCA-proficient settings, suggesting incomplete synergy even when TE reactivation is present.¹⁰ The vulnerability revealed in the study may not be generalized broadly without clear functional validation, because TE reactivation does not always trigger DNA damage or immune responses. Other TE-derived nucleic acid species, such as RNA:DNA hybrids, may confound the effects, and resistance mechanisms in clinical settings can further reduce PARPi efficacy. To establish this approach as a reliable therapeutic strategy, future studies must clarify the causal role of TE activity, identify key downstream sensors like melanoma differentiation-associated protein 5, stimulator of interferon genes, or retinoic acid-inducible gene-I, and define the tumor-specific contexts that support synthetic lethality beyond BRCA-deficient cancers.

The study revealed a new synthetic lethality mechanism, namely, cancers with Polycomb group mutations and TE reactivation can be targeted by PARPi through TE-mediated genome instability, thereby offering a promising therapeutic strategy beyond the classical BRCA-related models.

Conflict-of-interest disclosure: The author declares no competing financial interests.