KAT7 is a therapeutic vulnerability of MLL rearranged acute myeloid leukemia

Histone lysine acetyltransferases (HATs/KATs) catalyze the transfer of acetyl groups from acetyl-CoA to lysines of core histones, playing a central role in transcriptional regulation, which when dysregulated lead to diseases. Through genome-wide CRISPR-Cas9 screens we recently identified several HATs of the MYST family that show cell-specific essentiality and therefore may represent potential novel therapeutic targets for acute myeloid leukaemia (AML). Here we investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by MLL fusions. We find that KAT7 loss leads to a rapid and dramatic global reduction in both H3K14ac and H4K12ac in association with reduced proliferation, increased apoptosis or enhanced differentiation of AML cells driven by MLL-X fusions. We go on to show that KAT7 activity is required for the recruitment of the MLL-fusion associated adaptor proteins such as BRD4 to gene promoters, which are critical for the maintenance of the MLL-AF9 transcriptional programme. Our findings propose that KAT7 is a plausible therapeutic target for this poor prognosis subtype of AML.