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

Namyoung Jung, Bo Dai, Andrew J. Gentles, Ravindra Majeti () and Andrew P. Feinberg ()
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Namyoung Jung: Center for Epigenetics, 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

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9489

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