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An LSC epigenetic signature is largely mutation independent and implicates the HOXA cluster in AML pathogenesis

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  • Namyoung Jung

    (Center for Epigenetics, Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Bo Dai

    (Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University)

  • Andrew J. Gentles

    (and Center for Cancer Systems Biology, School of Medicine, Stanford University)

  • Ravindra Majeti

    (Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University)

  • Andrew P. Feinberg

    (Center for Epigenetics, Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

Abstract

Acute myeloid leukaemia (AML) is characterized by subpopulations of leukaemia stem cells (LSCs) that are defined by their ability to engraft in immunodeficient mice. Here we show an LSC DNA methylation signature, derived from xenografts and integration with gene expression that is comprised of 71 genes and identifies a key role for the HOXA cluster. Most of the genes are epigenetically regulated independently of underlying mutations, although several are downstream targets of epigenetic modifier genes mutated in AML. The LSC epigenetic signature is associated with poor prognosis independent of known risk factors such as age and cytogenetics. Analysis of early haematopoietic progenitors from normal individuals reveals two distinct clusters of AML LSC resembling either lymphoid-primed multipotent progenitors or granulocyte/macrophage progenitors. These results provide evidence for DNA methylation variation between AML LSCs and their blast progeny, and identify epigenetically distinct subgroups of AML likely reflecting the cell of origin.

Suggested Citation

  • Namyoung Jung & Bo Dai & Andrew J. Gentles & Ravindra Majeti & Andrew P. Feinberg, 2015. "An LSC epigenetic signature is largely mutation independent and implicates the HOXA cluster in AML pathogenesis," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9489
    DOI: 10.1038/ncomms9489
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    Cited by:

    1. Anna A Schönherz & Julie Støve Bødker & Alexander Schmitz & Rasmus Froberg Brøndum & Lasse Hjort Jakobsen & Anne Stidsholt Roug & Marianne T Severinsen & Tarec C El-Galaly & Paw Jensen & Hans Erik Joh, 2020. "Normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact," PLOS ONE, Public Library of Science, vol. 15(4), pages 1-21, April.
    2. Lina Liu & Ana Vujovic & Nandan P. Deshpande & Shashank Sathe & Govardhan Anande & He Tian Tony Chen & Joshua Xu & Mark D. Minden & Gene W. Yeo & Ashwin Unnikrishnan & Kristin J. Hope & Yu Lu, 2022. "The splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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