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Enhancer DNA methylation in acute myeloid leukemia and myelodysplastic syndromes

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Abstract

DNA methylation (CpG methylation) exerts an important role in normal differentiation and proliferation of hematopoietic stem cells and their differentiated progeny, while it has also the ability to regulate myeloid versus lymphoid fate. Mutations of the epigenetic machinery are observed in hematological malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) resulting in hyper- or hypo-methylation affecting several different pathways. Enhancers are cis-regulatory elements which promote transcription activation and are characterized by histone marks including H3K27ac and H3K4me1/2. These gene subunits are target gene expression ‘fine-tuners’, are differentially used during the hematopoietic differentiation, and, in contrast to promoters, are not shared by the different hematopoietic cell types. Although the interaction between gene promoters and DNA methylation has extensively been studied, much less is known about the interplay between enhancers and DNA methylation. In hematopoiesis, DNA methylation at enhancers has the potential to discriminate between fetal and adult erythropoiesis, and also is a regulatory mechanism in granulopoiesis through repression of neutrophil-specific enhancers in progenitor cells during maturation. The interplay between DNA methylation at enhancers is disrupted in AML and MDS and mainly hyper-methylation at enhancers raising early during myeloid lineage commitment is acquired during malignant transformation. Interactions between mutated epigenetic drivers and other oncogenic mutations also affect enhancers’ activity with final result, myeloid differentiation block. In this review, we have assembled recent data regarding DNA methylation and enhancers’ activity in normal and mainly myeloid malignancies.

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Authors and Affiliations

  1. Blood Bank, Preveza General Hospital, Preveza, Greece

    Leonidas Benetatos

  2. Molecular Biology Laboratory, Ioannina University Hospital, Ioannina, Greece

    George Vartholomatos

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  1. Leonidas Benetatos
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LB and GV collected data and wrote the paper.

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Correspondence to Leonidas Benetatos.

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Benetatos, L., Vartholomatos, G. Enhancer DNA methylation in acute myeloid leukemia and myelodysplastic syndromes. Cell. Mol. Life Sci. 75, 1999–2009 (2018). https://doi.org/10.1007/s00018-018-2783-2

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