The Transposable Element-PARP Axis Underpins Synthetic Lethality and Immunogenic Vulnerability in Blood Cancer.

Transposable elements (TEs) are emerging regulators of hematopoiesis and leukemia, creating vulnerabilities exploitable for therapy. Recent evidence shows that TE reactivation induces innate immune signalling, DNA damage responses and dependence on Poly(ADP-ribose) polymerase (PARP)-mediated protection, enabling synthetic lethality with PARP inhibition even in homologous-recombination-proficient leukemias with epigenetic gene mutations. In this article, we highlight the biology underpinning this novel TE-PARP axis, its therapeutic implications and strategies to expand beyond HR-deficient cancers through rational combinations with immunotherapy and refined patient stratification.