Understanding the molecular pathogenesis of MLL fusion protein (MLL-FP) leukaemia has generated epigenetic therapies that have improved clinical outcomes for this often incurable disease. The use of Menin inhibitors (MENi) has shown great clinical promise resulting in several phase 1/2 clinical trials. However, acquired resistance to MENi by both genetic and epigenetic mechanisms highlight the need to further improve efficacy of treatment.
We have previously shown that Leukemic Stem Cells (LSCs) are reliant on KAT7, a member of the MYST2 histone acetyltransferase complex. Loss of KAT7 by genetic knockout or small molecule inhibition drives differentiation and cell death in LSCs and leukemic blasts. Recent pharmacological advances have lead to development of PF-9363, a small molecule inhibitor of KAT6A, KAT6B and KAT7. While PF-9363, shows promise in solid cancers, efficacy in leukemia has not yet been characterized.
Using proteomics, chromatin immunoprecipitation and RNA sequencing we define the individual and combined contribution of KAT6A, KAT6B and KAT7 in MLL-FP leukemia and identify potent synergy with combined MYST and Menin inhibition. Whilst inhibition of KAT6A/B is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, increases therapeutic efficacy and provides an orthogonal route to targeting the MLL-FP transcriptional program. We show that KAT7 interacts with Menin and the MLL complex where it co-localises at chromatin to co-regulate the MLL-FP transcriptional program. Combined Menin and MYST inhibition rapidly evict the MLL-FP from chromatin, potently represses oncogenic transcription and can overcome both primary and acquired resistance to Menin inhibitors.
These data reveal a new synergy between two chromatin-modifying complexes indispensable to MLL-FP leukemia, that can now be pharmacologically targeted. Ultimately, this work provides strong molecular rationale for clinical translation of combined MYST and Menin therapy in MLL-FP leukaemia.