Catalytic inhibition of KAT6 /KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia [RNA-seq]

Understanding the molecular pathogenesis of MLL leukaemia has led to the development of epigenetic therapies that have altered the natural history of this often-incurable disease. Here, using complementary genetic and pharmacological approaches, we define the individual and combined contribution of the MYST acetyltransferases, KAT6A, KAT6B and KAT7, to MLL fusion oncoprotein (MLL-FP) driven acute leukaemia. We show that inhibition of KAT6A/B is efficacious in some but not all MLL-FP pre-clinical models; however, simultaneous targeting of KAT7 increases the therapeutic effect. At a molecular level, KAT7 interacts with Menin and other members the MLL complex and we demonstrate that these epigenetic regulators are co-localised at chromatin where they co-regulate the oncogenic transcriptional program initiated and maintained by the MLL-FP. Catalytic inhibition of KAT6/KAT7 with the novel small molecule inhibitor PF-9363 provides an orthogonal route to Menin inhibition to disable the transcriptional activity of MLL-FP. This is of clinical importance as PF-9363 or genetic depletion of KAT7 is able to overcome both genetic and non-genetic acquired resistance to Menin inhibition. Moreover, combined inhibition of KAT6/KAT7 and Menin results in a rapid eviction of chromatin bound MLL-FP and a profound repression of the oncogenic transcriptional program resulting in marked synergistic benefit in pre-clinical models of primary resistance to single agent therapy. Together these data provide the molecular rationale for rapid clinical translation of combination therapy to further improve clinical outcomes in MLL-FP leukaemia.