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).
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
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Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here, we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2 knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single-cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested hepatocyte nuclear factor 4 alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of Sox9, a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.
