RNA Sequencing Analysis of control vs KDM4Ai treated cells as a monotherapy or in combination with PARPi

Leukaemic blasts share common pathological features with other cancers including genome instability and impaired DNA damage response and repair (DDR). The limited efficacy of DDR inhibitors, such as poly (ADP-ribose) polymerase inhibitors (PARPi) as single agents in acute myeloid leukaemia (AML) is partly owing to activation of alternative DDR pathways and cytotoxicity to healthy tissues. Their strengths may lie in combination strategies targeting other essential proteins required for leukaemogenesis. We have identified the histone demethylase, KDM4A, as a critical epigenetic regulator required for AML cell survival. Depletion of KDM4A causes aberrant DDR pathway activation and subsequent DNA damage. We hypothesised that KDM4A inhibitors (KDM4Ai) increase AML cell reliance on specific DDR pathways for survival and may sensitise them to PARPi. We aimed to analyse transcriptional profiling (RNA Seq) changes associated with varying concentrations of KDM4A inhibition in monotherapy and as a combination therapy with a single PARPi treatment following 36hrs treatment. In summary, our study identifies a novel potential therapeutic strategy for AML. KDM4Ai sensitises cells to PARPi through impairing further NHEJ repair and enhancing PARP trapping leading to selective leukaemic cell death. These results warrant future clinical evaluation of this promising combination strategy in AML and other cancers. Overall design: THP1 cells representitive of MLL-AF9 AML were treated for 36hrs with DMSO (Vehicle Control), ~IC50 KDM4Ai, High Conc. KDM4Ai, EC50 PARPi in monotherapy and combination of ~IC50 KDM4Ai and EC50 PARPi in triplicate