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.
Highlights
Acute myeloid leukaemia (AML) is characterized by subpopulations of leukaemia stem cells (LSCs) that are defined by their ability to engraft in immunodeficient mice
Studies investigating the cell of origin of human AML using surface immunophenotype and gene expression originally suggested AML LSCs arise from HSC10, but more recent analysis suggests they arise from committed progenitors, including lymphoid-primed multipotent progenitors (L-MPP) and GMP3
While AML LSC were originally described to be exclusively contained in the CD34 þ CD38 À subpopulation, recent reports have indicated that leukaemia-initiating cells can be detected in multiple compartments including both the CD34 þ CD38 þ and CD34 À subpopulations, usually at lower frequencies[3,4,5]
Summary
Acute myeloid leukaemia (AML) is characterized by subpopulations of leukaemia stem cells (LSCs) that are defined by their ability to engraft in immunodeficient mice. We and others have recently reported that leukaemogenic mutations arise in pre-leukaemic HSC that undergo further clonal evolution to give rise to AML LSC11–13, likely in downstream progenitors as has been demonstrated in chronic myeloid leukaemia (CML)[14] We address this question of the cell of origin directly by determining the epigenetic signature of engrafting LSC in AML. We have attempted to define epigenetic differences between LSC and their non-stem blast progeny by testing engraftment capability of fractionated leukaemic cells from AML patients, to define the critical core elements of this key malignant stem cell phenotype Through this approach, we define a methylation and gene expression-based epigenetic signature for LSC, and find it to be largely independent of genetic mutations and strongly implicating a role for the HOXA gene cluster.
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