Increased methylation upstream of the MEG3 promotor is observed in acute myeloid leukemia patients with better overall survival

• Published in: Clinical epigenetics Vol. 11; no. 1; p. 50
• Main Authors: Sellers, Zachariah Payne, Bolkun, Lukasz, Kloczko, Janusz, Wojtaszewska, Marzena Liliana, Lewandowski, Krzysztof, Moniuszko, Marcin, Ratajczak, Mariusz Z, Schneider, Gabriela
• Format: Journal Article
• Language: English
• Published: Germany BioMed Central Ltd 15.03.2019; BioMed Central; BMC
• Subjects: Acute myelocytic leukemia; Acute myeloid leukemia; Adult; Base sequence; Binding sites; Bisulfite; Calcium-Binding Proteins - genetics; Cancer stem cells; Cancer therapies; Chromatin; CpG islands; Deoxyribonucleic acid; Development and progression; DLK1-MEG3; DNA; DNA Methylation; DNA sequencing; Epigenetics; Female; Future predictions; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Genetic engineering; Genomic Imprinting; Hematopoietic stem cells; Humans; Imprinting; Induction Chemotherapy; Induction therapy; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukocytes (mononuclear); Ligands; Male; Medical prognosis; Membrane Proteins - genetics; Methylation; MicroRNA; Middle Aged; miRNA; miRNAs; Myeloid leukemia; Novels; Nucleotide sequence; Patients; Pilot Projects; Preadipocyte factor 1; Prognosis; Promoter Regions, Genetic; RNA, Long Noncoding - genetics; Sequence Analysis, DNA; Stem cells; Sulfites; Survival Analysis; Young Adult; miRNAs; Cancer stem cells; DLK1-MEG3; Imprinting; Leukemia
• ISSN: 1868-7075; 1868-7083; 1868-7083; 1868-7075
• DOI: 10.1186/s13148-019-0643-z

The delta-like non-canonical Notch ligand 1 (DLK1)-maternally expressed 3(MEG3) locus (DLK1-MEG3 locus) plays a critical role in the maintenance and differentiation of hematopoietic stem cells. Accumulating evidence implicates the imprinted genes from this locus, DLK1 and MEG3, in the development and progression of acute myeloid leukemia (AML). However, the contribution of this locus to the treatment response of patients and their survival is unknown. DNA methylation of select CG dinucleotide-containing amplicons (CpG sites) within the DLK1-MEG3 locus and within differentially methylated regions of other imprinted loci was assessed in the mononuclear cells of 45 AML patients by combined bisulfite restriction analysis. Methylation results were compared with patient response to first-round induction therapy and overall survival. Multivariable analysis was employed to identify independent prognostic factors for patient overall survival in AML. Increased methylation at CpG sites within the MEG3 promotor region was observed in AML patients having longer overall survival. In addition, patients with shorter overall survival had increased expression of DLK1 and MEG3, and methylation at the MEG3-DMR CpG site inversely correlated with MEG3 expression. Multivariable analysis revealed that methylation at CG9, a non-imprinted CpG site within the MEG3 promotor region which contains a CCCTC-binding factor (CTCF)-binding DNA sequence, is an independent prognostic factor for the overall survival of AML patients. The results of our pilot study underscore the importance of the DLK1-MEG3 locus in AML development and progression. We identify CG9 methylation as an independent prognostic factor for AML patient survival, which suggests that distinct miRNA signatures from the DLK1-MEG3 locus could reflect varying degrees of cell stemness and present novel opportunities for personalized therapies in the future. These data provide a foundation for future studies into the role of higher-order chromatin structure at DLK1-MEG3 in AML.