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Acute myeloid leukemia

KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL rearrangements

Abstract

Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-CoA to lysine residues of histones and play a central role in transcriptional regulation in diverse biological processes. Dysregulation of HAT activity can lead to human diseases including developmental disorders and cancer. Through genome-wide CRISPR-Cas9 screens, we identified several HATs of the MYST family as fitness genes for acute myeloid leukemia (AML). Here we investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by the MLL-X gene fusions. We found that KAT7 loss leads to a rapid and complete loss of both H3K14ac and H4K12ac marks, in association with reduced proliferation, increased apoptosis, and differentiation of AML cells. Acetyltransferase activity of KAT7 is essential for the proliferation of these cells. Mechanistically, our data propose that acetylated histones provide a platform for the recruitment of MLL-fusion-associated adaptor proteins such as BRD4 and AF4 to gene promoters. Upon KAT7 loss, these factors together with RNA polymerase II rapidly dissociate from several MLL-fusion target genes that are essential for AML cell proliferation, including MEIS1, PBX3, and SENP6. Our findings reveal that KAT7 is a plausible therapeutic target for this poor prognosis AML subtype.

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Fig. 1: Loss of KAT7 exhibits antileukemic effects in vitro and in vivo.
Fig. 2: Catalytic activity of KAT7 is required for leukemic maintenance.
Fig. 3: Transcriptomic profiling of KAT7 KO in MOLM-13 (MLL-AF9), OCI-AML3 (MLL WT).
Fig. 4: Transcriptomic profiling of the acute phase of KAT7 depletion in MOLM-13 using the degron system.
Fig. 5: KAT7 binds to and is required for expression of a subset of MLL-AF9 targets.
Fig. 6: KAT7-dependent recruitment of BRD4 and SEC complex to a subset of MLL-AF9 spreading genes.

Data availability

RNA-seq and ChIP-seq data are available from Gene Expression Omnibus under accession number GSE133516.

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Acknowledgements

This work was funded by the Wellcome Trust (WT206194), the Kay Kendall Leukaemia Fund (KKL920), Bloodwise (17006), Takeda Science Foundation, and Exonate Ltd. K.T. was funded by a Wellcome Trust Sir Henry Wellcome Fellowship (grant reference RG94424). G.S.V. was funded by a Cancer Research UK Senior Cancer Fellowship (C22324/A23015) and a Wellcome Trust Senior Fellowship in Clinical Science (WT095663MA). We thank Bee Ling Ng, Jennifer Graham, Christopher Hall, and Sam Thompson from the Wellcome Sanger Institute Cytometry Core Facility team for help with flow cytometry. We are grateful to the staff of the Sanger Institute Research Support Facility for help with mouse experiments and the staff of the Sanger Institute Core Sequencing facility for sequencing. We thank Mathew Garnett for providing the Nomo-1 cell line, Chris Vakoc for RN2 and MA9 cell lines, Pedro for his help compiling figures using Adobe Illustrate and Josep Nomdedeu for help advices in writing the manuscript.

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KY conceived the study and designed the experiments. YZA primarily performed the experiments and analyzed the data. M.Gu and SHO conducted bioinformatic analyses. EDB performed and analyzed the in vivo mouse studies. MG, EDB, and DA performed ChIP-qPCR and CRISPR validation studies. YT and JC performed cell proliferation assays. XC advised on ChIP experiments. JY, BJPH, MG, and KT helped with data interpretation and direction. YZA, MG, JY, GSV, and KY wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to George Vassiliou or Kosuke Yusa.

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GSV is a consultant for Kymab and Oxstem. All the remaining authors declare no conflict of interest.

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Au, Y.Z., Gu, M., De Braekeleer, E. et al. KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL rearrangements. Leukemia 35, 1012–1022 (2021). https://doi.org/10.1038/s41375-020-1001-z

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