Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukaemia stem-like cells
- University of Cambridge, United Kingdom
- Brunel University London, United Kingdom
Abstract
Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective white blood cell differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutation and by hijacking normal chromatin regulation. Kat2a is a histone acetyltransferase central to promoter activity, that we recently associated with stability of pluripotency networks, and identified as a genetic vulnerability in AML. Through combined chromatin profiling and single-cell transcriptomics of a conditional knockout mouse, we demonstrate that Kat2a contributes to leukemia propagation through preservation of leukemia stem-like cells. Kat2a loss impacts transcription factor binding and reduces transcriptional burst frequency in a subset of gene promoters, generating enhanced variability of transcript levels. Destabilization of target programs shifts leukemia cell fate out of self-renewal into differentiation. We propose that control of transcriptional variability is central to leukemia stem-like cell propagation, and establish a paradigm exploitable in different tumors and distinct stages of cancer evolution.
Data availability
All single-cell RNAseq data and ChIPseq data were deposited in GEO (SuperSeries GSE118769).
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Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cellsNCBI Gene Expression Omnibus, GSE118769.
Article and author information
Author details
Funding
Kay Kendall Leukaemia Fund (KKL888)
- Cristina Pina
Lady Tata Memorial Trust (PhD studentship)
- Shikha Gupta
Rosetrees Trust (PhD studentship)
- Liliana Arede
Isaac Newton Trust
- Cristina Pina
European Commission (800274)
- Keti Zeka
Wellcome (University of Cambridge ISSF)
- Cristina Pina
Wellcome (Cambridge/DBT Lectureship)
- Sudhakaran Prabakaran
Associazione Italiana per la Ricerca sul Cancro
- Keti Zeka
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were kept in an SPF animal facility, and all experimental work was carried out under UK Home Office regulations. Animal research was regulated under the Animals (Scientific Procedures) Act 1986 Amendment Regulations 2012 following ethical review by the University of Cambridge Animal Welfare and Ethical Review Body (AWERB).
Reviewing Editor
- Jian Xu, University of Texas Southwestern Medical Center, United States
Publication history
- Received: September 9, 2019
- Accepted: January 24, 2020
- Accepted Manuscript published: January 27, 2020 (version 1)
- Version of Record published: February 24, 2020 (version 2)
Copyright
© 2020, Domingues et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukaemia stem-like cells
eLife 9:e51754.
https://doi.org/10.7554/eLife.51754
Further reading
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Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3, encoded by KMT2C) histone methyltransferase occur in a range of solid tumors, and heterozygous deletions encompassing KMT2C occur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating the Cdkn2a tumor suppressor locus. Disruption of Kmt2c cooperates with Myc overexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to the Cdkn2a locus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded tumor suppressors p16/Ink4a and p19/Arf. Conversely, elevated KMT2C expression increases its binding to the CDKN2A locus and co-activates gene transcription. Endogenous Kmt2c restoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations in KMT2C and CDKN2A were associated with similar transcriptional profiles in human HCC samples. These results collectively point to a new mechanism for disrupting CDKN2A activity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network.
