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Cells 2018, 7(9), 138; https://doi.org/10.3390/cells7090138

Relationship between Altered miRNA Expression and DNA Methylation of the DLK1-DIO3 Region in Azacitidine-Treated Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia with Myelodysplasia-Related Changes

1
Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague 2, Czech Republic
2
General University Hospital, 128 08 Prague, Czech Republic
*
Author to whom correspondence should be addressed.
Received: 14 August 2018 / Revised: 5 September 2018 / Accepted: 11 September 2018 / Published: 14 September 2018
(This article belongs to the Special Issue Regulatory microRNA)
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Abstract

The DLK1–DIO3 region contains a large miRNA cluster, the overexpression of which has previously been associated with myelodysplastic syndromes (MDS). To reveal whether this overexpression is epigenetically regulated, we performed an integrative analysis of miRNA/mRNA expression and DNA methylation of the regulatory sequences in the region (promoter of the MEG3 gene) in CD34+ bone marrow cells from the patients with higher-risk MDS and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), before and during hypomethylating therapy with azacytidine (AZA). Before treatment, 50% of patients showed significant miRNA/mRNA overexpression in conjunction with a diagnosis of AML-MRC. Importantly, increased level of MEG3 was associated with poor outcome. After AZA treatment, the expression levels were reduced and were closer to those seen in the healthy controls. In half of the patients, we observed significant hypermethylation in a region preceding the MEG3 gene that negatively correlated with expression. Interestingly, this hypermethylation (when found before treatment) was associated with longer progression-free survival after therapy initiation. However, neither expression nor methylation status were associated with future responsiveness to AZA treatment. In conclusion, we correlated expression and methylation changes in the DLK1–DIO3 region, and we propose a complex model for regulation of this region in myelodysplasia. View Full-Text
Keywords: microRNA; myelodysplastic syndromes; acute myeloid leukemia; azacitidine; 14q32; MEG3 microRNA; myelodysplastic syndromes; acute myeloid leukemia; azacitidine; 14q32; MEG3
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Merkerova, M.D.; Remesova, H.; Krejcik, Z.; Loudova, N.; Hrustincova, A.; Szikszai, K.; Cermak, J.; Jonasova, A.; Belickova, M. Relationship between Altered miRNA Expression and DNA Methylation of the DLK1-DIO3 Region in Azacitidine-Treated Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia with Myelodysplasia-Related Changes. Cells 2018, 7, 138.

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