Fig. 2
From: Therapeutic potential of inhibiting histone 3 lysine 27 demethylases: a review of the literature
KDM6A/B inhibition in acute myeloid leukaemia. KDM6A and KDM6B have contrasting roles in the pathogenesis of acute myeloid leukaemia (AML). Increased KDM6B expression and occupancy at gene promoter regions in AML drives the transcription of genes involved in regulating the cell cycle, DNA replication, apoptosis and cellular differentiation, leading to the proliferation and colony formation of AML cells. Inhibition of KDM6B therefore attenuates AML cell proliferation and colony formation by promoting repressive H3K27 trimethylation, which downregulates the expression of these oncogenic genes. Contrastingly, through H3K27 demethylation, KDM6A upregulates the expression of the drug influx transporter ENT1, allowing the cellular entry of the chemotherapeutic agents cytarabine and daunorubicin and the consequent inhibition of AML cell proliferation and colony formation. Inhibition of KDM6A with GSK-J4 renders AML cells resistant to these chemotherapeutic agents by suppressing their cellular uptake through the downregulation of ENT1. This figure was created in BioRender.com