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

While Polycomb group (PcG) proteins frequently mutated in cancers play important roles in governing expression of both coding and non-coding genomes, very little is known about the molecular profiles and therapeutic potentials of targeting deregulated non-coding genomes in these cancers. Here we show that co-inactivation of Asxl1 and Ezh2 in haematopoietic stem and progenitor cells results in highly penetrant haematological malignancies of myeloid or lymphoid lineages as observed in corresponding human diseases with marked reactivation of transposable elements (TEs) and DNA damage responses (DDR). Using both mouse models and primary patient samples, we further demonstrate that Asxl1/Ezh2 mutated cells are highly sensitive to PARP inhibitor (PARPi) that led to excessive DNA damage and significantly extended disease latency. Intriguingly PARPi sensitivity can be overridden by reverse transcriptase inhibitors that specifically interrupt the life cycle of TEs. Together, this study reveals reactivated TEs as novel therapeutic targets for PARPi-induced synthetic lethal targeting of cancers carrying PcG epigenetic mutations.