Transposable elements as novel therapeutic targets for PARPi-induced synthetic lethality in haematological malignancies with PcG epigenetic mutations

Polycomb group (PcG) proteins play an important role in governing expression of transposable elements (TEs), which recently find to involve in various key cellular processes including gene regulation, DNA damage responses (DDR) and inflammatory responses. Here we show that co-inactivation of Asxl1 and Ezh2 in mouse haematopoietic stem cells mimic human diseases resulting in highly penetrant haematological malignancies of myeloid or lymphoid lineages with specific and significant reactivation of TEs and DDR. Using both mouse models and primary patient samples, we showed that Asxl1/Ezh2 mutated leukaemia cells were highly sensitive to PARP inhibitor (PARPi) treatment that led to excessive DNA damage and cell death. PARPi significantly extended disease latency in vivo, which intriguingly can be overridden by reverse transcriptase inhibitors that specifically interrupt the life cycle of reactivated TEs. Together, this study reveals TEs as novel therapeutic targets for PARPi-induced synthetic lethal targeting of cancers carrying PcG epigenetic mutations.