Loss-of-function mutations in PRC genes, such as EZH2 and ASXL1, lead to epigenetic dysregulation, which leads to the aberrant activation of TEs and accumulation of DNA damage. This increased genomic instability sensitizes the cancer cells to PARPis, which further impairs DNA repair and pushes the cells toward lethal levels of damage. Unlike the classic BRCA-deficient model of PARPi sensitivity, this mechanism depends on TE activity because blocking reverse transcription of TEs can rescue the cells, highlighting a novel therapeutic strategy for targeting PRC-mutated blood cancers. The illustration was created using the National Institute of Allergy and Infectious Diseases NIH BioArt Source (bioart.niaid.nih.gov/bioart [images 372, 171, 172, 72, 329, 452, 124, and 71]).