Abstract
BackgroundThe 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.MethodsDNA 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.ResultsIncreased 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.ConclusionsThe 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.
Highlights
Genomic imprinting is an epigenetic process governed by complementary chromatin structures inherited from the mother and father
Increased methylation at the MEG3 promotor region is found in acute myeloid leukemia (AML) patients with better overall survival To investigate the relationship between methylation at the delta-like non-canonical Notch ligand 1 (DLK1)-MEG3 locus and patient outcomes in AML, we assessed the methylation of four CpG sites within this locus (Fig. 1a) in AML patient peripheral blood mononuclear cells (MNCs) and compared our results with patient overall survival (OS) and first-round induction therapy response (IR)
At least seven CCCTC-binding factor (CTCF)-binding sites exist within DLK1-MEG3 [40], and three of these CTCF-binding sites are located within CG7, CG8, and CG9 (Table 4)
Summary
Genomic imprinting is an epigenetic process governed by complementary chromatin structures inherited from the mother and father. With the help of long non-coding RNAs (lncRNAs), differential covalent modifications of maternally and paternally inherited DNA and histone proteins control certain gene dosages in a parent-of-origin-specific manner [1]. The human genome contains more than 100 such imprinted genes which cluster around CG-rich regions of DNA These regions, known as differentially methylated regions (DMRs), exhibit unique patterns of methylation at CG cytosine residues based on the parental origin of the chromosome. It was soon realized that a second paternally imprinted locus housing IGN genes, Dlk1-Meg, was responsible for the restricted growth and development of bimaternal embryos [10], and a high efficiency of bimaternal mouse generation was later achieved via genetic manipulation mimicking somatic imprinting of both loci [11]. The contribution of this locus to the treatment response of patients and their survival is unknown
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