Dataset Information

The epigenome of AML stem and progenitor cells.

ABSTRACT: Acute myeloid leukemia (AML) is sustained by a population of cancer stem cells (CSCs or cancer-initiating cell). The mechanisms underlying switches from CSCs to non-CSCs in vivo remain to be understood. We address this issue in AML from the aspect of epigenetics using genome-wide screening for DNA methylation and selected histone modifications. We found no major differences in DNA methylation, especially in promoter CpG islands, between CSCs and non-CSCs. By contrast, we found thousands of genes that change H3K4me3 and/or H3K27me3 status between stem and progenitor cells as well as between progenitor and mature cells. Stem cell related pathways and proliferation or metabolism related pathways characterize genes differentially enriched for H3K4me3/H3K27me3 in stem and progenitor populations. Bivalent genes in stem cells are more plastic during differentiation and are more likely to lose H3K4me3 than to lose H3K27me3, consistent with increasingly closed chromatin state with differentiation. Our data indicates that histone modifications but not promoter DNA methylation are involved in switches from CSCs to non-CSCs in AML.

SUBMITTER: Yamazaki J

PROVIDER: S-EPMC3549884 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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The epigenome of AML stem and progenitor cells.

Yamazaki Jumpei J Estecio Marcos R MR Lu Yue Y Long Hai H Malouf Gabriel G GG Graber David D Huo Yujia Y Ramagli Louis L Liang Shoudan S Kornblau Steven M SM Jelinek Jaroslav J Issa Jean-Pierre J JP

Epigenetics 20121218 1

Acute myeloid leukemia (AML) is sustained by a population of cancer stem cells (CSCs or cancer-initiating cell). The mechanisms underlying switches from CSCs to non-CSCs in vivo remain to be understood. We address this issue in AML from the aspect of epigenetics using genome-wide screening for DNA methylation and selected histone modifications. We found no major differences in DNA methylation, especially in promoter CpG islands, between CSCs and non-CSCs. By contrast, we found thousands of genes ...[more]

PMID: 23249680

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Project description:Understanding the unique phenotypes and complex signaling pathways of leukemia stem cells (LSCs) will provide insights and druggable targets that can be used to eradicate acute myeloid leukemia (AML). Current work on AML LSCs is limited by the number of parameters that conventional flow cytometry (FCM) can analyze because of cell autofluorescence and fluorescent dye spectral overlap. Single-cell mass cytometry (CyTOF) substitutes rare earth elements for fluorophores to label antibodies, which allows measurements of up to 120 parameters in single cells without correction for spectral overlap. The aim of this study was the evaluation of intracellular signaling in antigen-defined stem/progenitor cell subsets in primary AML. CyTOF and conventional FCM yielded comparable results on LSC phenotypes defined by CD45, CD34, CD38, CD123, and CD99. Intracellular phosphoprotein responses to ex vivo cell signaling inhibitors and cytokine stimulation were assessed in myeloid leukemia cell lines and one primary AML sample. CyTOF and conventional FCM results were confirmed by western blotting. In the primary AML sample, we investigated the cell responses to ex vivo stimulation with stem cell factor and BEZ235-induced inhibition of PI3K and identified activation patterns in multiple PI3K downstream signaling pathways including p-4EBP1, p-AKT, and p-S6, particularly in CD34(+) subsets. We evaluated multiple signaling pathways in antigen-defined subpopulations in primary AML cells with FLT3-ITD mutations. The data demonstrated the heterogeneity of cell phenotype distribution and distinct patterns of signaling activation across AML samples and between AML and normal samples. The mTOR targets p-4EBP1 and p-S6 were exclusively found in FLT3-ITD stem/progenitor cells, but not in their normal counterparts, suggesting both as novel targets in FLT3 mutated AML. Our data suggest that CyTOF can identify functional signaling pathways in antigen-defined subpopulations in primary AML, which may provide a rationale for designing therapeutics targeting LSC-enriched cell populations.

Dataset Information

The epigenome of AML stem and progenitor cells.

Publications

The epigenome of AML stem and progenitor cells.

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