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

Jung N, Dai B, Gentles AJ, Majeti R, Feinberg AP - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

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.

Show MeSH

Related in: MedlinePlus

AML LSCs and Blasts exhibit epigenetic differences that define an LSC epigenetic signature.Plots of DMRs indicating genomic loci for REC8 (a), HOXA9 (b), HOXA7 (c) and HOXA10 (d), four LSC epigenetic signature genes that are hypomethylated and upregulated in LSC. Top: level of CpG methylation (Beta) of each sample for the region; middle: CpG density (curve), CpG sites (black tick marks) and CpG islands (red lines); bottom: gene annotation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4633733&req=5

f1: AML LSCs and Blasts exhibit epigenetic differences that define an LSC epigenetic signature.Plots of DMRs indicating genomic loci for REC8 (a), HOXA9 (b), HOXA7 (c) and HOXA10 (d), four LSC epigenetic signature genes that are hypomethylated and upregulated in LSC. Top: level of CpG methylation (Beta) of each sample for the region; middle: CpG density (curve), CpG sites (black tick marks) and CpG islands (red lines); bottom: gene annotation.

Mentions: We compared our LSC epigenetic signature with the LSC gene expression signatures from previous studies56. Only six out of 71 genes were found in these earlier studies, suggesting most of the genes identified here comprise a novel signature for LSC defined first by DMR analysis and refined by gene expression differences. One gene in this signature, REC8, which encodes a kleisin family protein that is associated with the cohesin complex, was hypomethylated and transcriptionally upregulated in LSC (Fig. 1a and Supplementary Data 2). Notably, mutations of components of the cohesin complex have been identified in AML and other tumour types1920. Further experiments will be necessary to determine if increased expression of REC8 alters cohesin complex functions in LSC. We also identified HOXA5, HOXA6, HOXA7, HOXA9 and HOXA10 in the LSC epigenetic signature (Fig. 1b–d and Supplementary Data 2). These HOXA cluster genes were hypomethylated and highly expressed in LSC (Supplementary Data 2). Notably, HOXA9 showed hypomethylation and increased expression in LSC (Fig. 1b and Supplementary Data 2), and aberrant expression of HOXA9 is known to be involved in increased proliferation of HSPCs and leukaemogenesis, suggesting a critical role in LSC activity21222324.


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

Jung N, Dai B, Gentles AJ, Majeti R, Feinberg AP - Nat Commun (2015)

AML LSCs and Blasts exhibit epigenetic differences that define an LSC epigenetic signature.Plots of DMRs indicating genomic loci for REC8 (a), HOXA9 (b), HOXA7 (c) and HOXA10 (d), four LSC epigenetic signature genes that are hypomethylated and upregulated in LSC. Top: level of CpG methylation (Beta) of each sample for the region; middle: CpG density (curve), CpG sites (black tick marks) and CpG islands (red lines); bottom: gene annotation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4633733&req=5

f1: AML LSCs and Blasts exhibit epigenetic differences that define an LSC epigenetic signature.Plots of DMRs indicating genomic loci for REC8 (a), HOXA9 (b), HOXA7 (c) and HOXA10 (d), four LSC epigenetic signature genes that are hypomethylated and upregulated in LSC. Top: level of CpG methylation (Beta) of each sample for the region; middle: CpG density (curve), CpG sites (black tick marks) and CpG islands (red lines); bottom: gene annotation.
Mentions: We compared our LSC epigenetic signature with the LSC gene expression signatures from previous studies56. Only six out of 71 genes were found in these earlier studies, suggesting most of the genes identified here comprise a novel signature for LSC defined first by DMR analysis and refined by gene expression differences. One gene in this signature, REC8, which encodes a kleisin family protein that is associated with the cohesin complex, was hypomethylated and transcriptionally upregulated in LSC (Fig. 1a and Supplementary Data 2). Notably, mutations of components of the cohesin complex have been identified in AML and other tumour types1920. Further experiments will be necessary to determine if increased expression of REC8 alters cohesin complex functions in LSC. We also identified HOXA5, HOXA6, HOXA7, HOXA9 and HOXA10 in the LSC epigenetic signature (Fig. 1b–d and Supplementary Data 2). These HOXA cluster genes were hypomethylated and highly expressed in LSC (Supplementary Data 2). Notably, HOXA9 showed hypomethylation and increased expression in LSC (Fig. 1b and Supplementary Data 2), and aberrant expression of HOXA9 is known to be involved in increased proliferation of HSPCs and leukaemogenesis, suggesting a critical role in LSC activity21222324.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

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.

Show MeSH
Related in: MedlinePlus