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).

The following data sets were generated

Article and author information

Author details

  1. Ana Filipa Domingues

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Rashmi Kulkarni

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. George Giotopoulos

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Shikha Gupta

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Laura Vinnenberg

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Liliana Arede

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Elena Foerner

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Mitra Khalili

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Rita Romano Adao

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Ayona Johns

    Division of Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Shengjiang Tan

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Keti Zeka

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Brian J Huntly

    Department of Haematology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Sudhakaran Prabakaran

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Cristina Pina

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    cp533@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2575-6301

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.

Reviewing Editor

  1. Jian Xu, University of Texas Southwestern Medical Center, United States

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).

Version history

  1. Received: September 9, 2019
  2. Accepted: January 24, 2020
  3. Accepted Manuscript published: January 27, 2020 (version 1)
  4. 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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  1. Ana Filipa Domingues
  2. Rashmi Kulkarni
  3. George Giotopoulos
  4. Shikha Gupta
  5. Laura Vinnenberg
  6. Liliana Arede
  7. Elena Foerner
  8. Mitra Khalili
  9. Rita Romano Adao
  10. Ayona Johns
  11. Shengjiang Tan
  12. Keti Zeka
  13. Brian J Huntly
  14. Sudhakaran Prabakaran
  15. Cristina Pina
(2020)
Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukaemia stem-like cells
eLife 9:e51754.
https://doi.org/10.7554/eLife.51754

Share this article

https://doi.org/10.7554/eLife.51754

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