KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL rearrangements
Author(s)
Type
Journal Article
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.
Date Issued
2021-04-01
Date Acceptance
2020-07-22
Citation
Leukemia, 2021, 35 (4), pp.1012-1022
ISSN
0887-6924
Publisher
Springer Science and Business Media LLC
Start Page
1012
End Page
1022
Journal / Book Title
Leukemia
Volume
35
Issue
4
Copyright Statement
© 2020, The Author(s) published by Springer Nature Limited. This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1038/s41375-020-1001-z
Subjects
Cell Line, Tumor
Myeloid Cells
Humans
Genetic Predisposition to Disease
Histone-Lysine N-Methyltransferase
Oncogene Proteins, Fusion
Histones
Apoptosis
Cell Differentiation
Epigenesis, Genetic
Gene Rearrangement
Protein Binding
Disease Management
Histone Acetyltransferases
Myeloid-Lymphoid Leukemia Protein
Leukemia, Myeloid, Acute
Promoter Regions, Genetic
Gene Knockout Techniques
Genetic Association Studies
Biomarkers, Tumor
Publication Status
Published
Date Publish Online
2020-08-06