CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors
Open Access
- 12 August 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Leukemia
- Vol. 26 (2), 244-254
- https://doi.org/10.1038/leu.2011.207
Abstract
The DNA hypomethylating drug decitabine maintains normal hematopoietic stem cell (HSC) self-renewal but induces terminal differentiation in acute myeloid leukemia (AML) cells. The basis for these contrasting cell fates, and for selective CpG hypomethylation by decitabine, is poorly understood. Promoter CpGs, with methylation measured by microarray, were classified by the direction of methylation change with normal myeloid maturation. In AML cells, the methylation pattern at maturation-responsive CpGs suggested at least partial maturation. Consistent with partial maturation, in gene expression analyses, AML cells expressed high levels of the key lineage-specifying factor CEBPA, but relatively low levels of the key late-differentiation driver CEBPE. In methylation analysis by mass spectrometry, CEBPE promoter CpGs that are usually hypomethylated during granulocyte maturation were significantly hypermethylated in AML cells. Decitabine-induced hypomethylation was greatest at these and other promoter CpGs that are usually hypomethylated with myeloid maturation, accompanied by cellular differentiation of AML cells. In contrast, decitabine-treated normal HSCs retained immature morphology, and methylation significantly decreased at CpGs that are less methylated in immature cells. High expression of lineage-specifying factor and aberrant epigenetic repression of some key late-differentiation driver genes distinguishes AML cells from normal HSCs, and could explain the contrasting differentiation and methylation responses to decitabine.This publication has 60 references indexed in Scilit:
- RUNX1 regulates corepressor interactions of PU.1Blood, 2011
- Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient miceJCI Insight, 2011
- DNA Methyltransferase 1 Is Essential for and Uniquely Regulates Hematopoietic Stem and Progenitor CellsCell Stem Cell, 2009
- Differentiation therapy of leukemia: 3 decades of developmentBlood, 2009
- Dysregulated gene expression networks in human acute myelogenous leukemia stem cellsProceedings of the National Academy of Sciences of the United States of America, 2009
- Aberrant DNA methylation is a dominant mechanism in MDS progression to AMLBlood, 2009
- Human acute leukemia cells injected in NOD/LtSz‐scid/IL‐2Rγ null mice generate a faster and more efficient disease compared to other NOD/scid‐related strainsInternational Journal of Cancer, 2008
- Epigenetic characterization of hematopoietic stem cell differentiation using miniChIP and bisulfite sequencing analysisProceedings of the National Academy of Sciences of the United States of America, 2007
- Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylationNucleic Acids Research, 2007
- High-throughput DNA methylation profiling using universal bead arraysGenome Research, 2006