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

ABSTRACT: Targeting the MYST acetyltransferases are an exciting therapeutic opportunity in acute myeloid leukaemia (AML). Here we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range of AML models showing that although KAT6A/B inhibition is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, markedly increases efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate oncogenic transcriptional programs. Focusing on MLL fusion oncoprotein (MLL-FP) AML, we show that inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of the MLL-FP. Combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Notably, KAT7 remains an important targetable dependency in acquired genetic/non-genetic resistance to Menin inhibition providing the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301145 | GEO | 2025/07/01

REPOSITORIES: GEO

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

Project description:Targeting the MYST acetyltransferases are an exciting therapeutic opportunity in acute myeloid leukaemia (AML). Here we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range of AML models showing that although KAT6A/B inhibition is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, markedly increases efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate oncogenic transcriptional programs. Focusing on MLL fusion oncoprotein (MLL-FP) AML, we show that inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of the MLL-FP. Combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Notably, KAT7 remains an important targetable dependency in acquired genetic/non-genetic resistance to Menin inhibition providing the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML.

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Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in acute myeloid leukaemia [CUT&Tag]

Project description:Understanding the molecular pathogenesis of MLL fusion oncoproteins (MLL-FP) has spawned epigenetic therapies that have improved clinical outcomes in this and other molecular subtypes of acute myeloid leukaemia (AML). Using genetic and pharmacological approaches, we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range of AML models. Whilst inhibition of KAT6A/B is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, increases the therapeutic efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate the oncogenic transcriptional program. Focussing on MLL-FP AML, we show that inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of the MLL-FP. Consequently, combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Moreover, PF-9363 or genetic depletion reveals that KAT7 remains an important targetable dependency in acquired genetic/non-genetic resistance to Menin inhibition. These data provide the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML.

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

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

Project description: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.

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