Targeting ADP-ribosylation by PARP inhibitors in acute myeloid leukaemia and related disorders

[Display omitted] Acute myeloid leukaemia (AML) is a highly heterogeneous disease characterized by uncontrolled proliferation, block in myeloid differentiation and recurrent genetic abnormalities. In the search of new effective therapies, identification of synthetic lethal partners of AML genetic alterations might represent a suitable approach to tailor patient treatment. Genetic mutations directly affecting DNA repair genes are not commonly present in AML. Nevertheless, several studies indicate that AML cells show high levels of DNA lesions and genomic instability. Leukaemia-driving oncogenes (e.g., RUNX1-RUNXT1, PML-RARA, TCF3-HLF, IDH1/2, TET2) or treatment with targeted agents directed against aberrant kinases (e.g., JAK1/2 and FLT3 inhibitors) have been associated with reduced DNA repair gene expression/activity that would render leukaemia blasts selectively sensitive to synthetic lethality induced by poly(ADP-ribose) polymerase inhibitors (PARPi). Thus, specific oncogenic chimeric proteins or gene mutations, rare or typically distinctive of certain leukaemia subtypes, may allow tagging cancer cells for destruction by PARPi. In this review, we will discuss the rationale for using PARPi in AML subtypes characterized by a specific genetic background and summarize the preclinical and clinical evidence reported so far on their activity when used as single agents or in combination with classical cytotoxic chemotherapy or with agents targeting AML-associated mutated proteins.