Increased methylation upstream of the MEG3 promotor is observed in acute myeloid leukemia patients with better overall survival.
Adult
Calcium-Binding Proteins
/ genetics
DNA Methylation
Female
Gene Expression Regulation, Neoplastic
Genomic Imprinting
Humans
Induction Chemotherapy
Leukemia, Myeloid, Acute
/ drug therapy
Male
Membrane Proteins
/ genetics
Middle Aged
Pilot Projects
Promoter Regions, Genetic
RNA, Long Noncoding
/ genetics
Sequence Analysis, DNA
Survival Analysis
Young Adult
Cancer stem cells
DLK1-MEG3
Imprinting
Leukemia
miRNAs
Journal
Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977
Informations de publication
Date de publication:
15 03 2019
15 03 2019
Historique:
received:
17
12
2018
accepted:
28
02
2019
entrez:
17
3
2019
pubmed:
17
3
2019
medline:
22
1
2020
Statut:
epublish
Résumé
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.
Sections du résumé
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
Identifiants
pubmed: 30876483
doi: 10.1186/s13148-019-0643-z
pii: 10.1186/s13148-019-0643-z
pmc: PMC6419839
doi:
Substances chimiques
Calcium-Binding Proteins
0
DLK1 protein, human
0
MEG3 non-coding RNA, human
0
Membrane Proteins
0
RNA, Long Noncoding
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
50Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK074720
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL112788
Pays : United States
Références
Cells. 2018 Sep 14;7(9):
pubmed: 30223454
Cold Spring Harb Perspect Biol. 2014 Feb 01;6(2):
pubmed: 24492710
Hum Mol Genet. 2002 Jan 1;11(1):77-86
pubmed: 11773001
Reproduction. 2006 Mar;131(3):481-8
pubmed: 16514191
Leukemia. 2015 Jun;29(6):1233-42
pubmed: 25703588
J Reprod Dev. 2008 Jun;54(3):177-82
pubmed: 18344616
Epigenetics. 2008 Jul-Aug;3(4):181-7
pubmed: 18698157
Nature. 2004 Apr 22;428(6985):860-4
pubmed: 15103378
Blood. 2009 Jul 30;114(5):937-51
pubmed: 19357394
Blood. 2010 Mar 18;115(11):2260-3
pubmed: 20089961
Leukemia. 2012 Sep;26(9):2052-60
pubmed: 22522792
Leuk Res. 2010 Feb;34(2):148-53
pubmed: 19595458
Dev Cell. 2006 Nov;11(5):711-22
pubmed: 17084362
Cell J. 2018 Apr;20(1):61-72
pubmed: 29308620
Stem Cell Rev Rep. 2018 Dec;14(6):823-836
pubmed: 29980981
J Clin Oncol. 2012 Jul 10;30(20):2441-8
pubmed: 22508825
Am J Physiol Regul Integr Comp Physiol. 2008 Jul;295(1):R189-96
pubmed: 18448610
Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20693-8
pubmed: 24297921
Leuk Res. 2014 Apr;38(4):443-6
pubmed: 24439565
Nature. 2010 May 13;465(7295):175-81
pubmed: 20418860
Leukemia. 2005 Aug;19(8):1404-10
pubmed: 15959531
Int J Cancer. 2005 Jul 10;115(5):690-700
pubmed: 15751035
Chromosome Res. 2005;13(8):809-18
pubmed: 16331412
Genes Dev. 1997 Jun 15;11(12):1596-604
pubmed: 9203585
Cell Stem Cell. 2016 Feb 4;18(2):214-28
pubmed: 26627594
Oncotarget. 2015 Oct 27;6(33):34691-703
pubmed: 26415227
Am J Transl Res. 2016 Feb 15;8(2):1091-9
pubmed: 27158395
Trends Genet. 2016 Jul;32(7):444-455
pubmed: 27235113
Blood. 2014 Mar 27;123(13):2066-74
pubmed: 24493669
Hum Mol Genet. 2007 Nov 1;16(21):2542-51
pubmed: 17636251
Oncol Res. 2018 Mar 5;26(2):297-305
pubmed: 28653609
Leukemia. 2009 Nov;23(11):2042-51
pubmed: 19641521
PLoS One. 2011;6(10):e26410
pubmed: 22039481
Oncotarget. 2017 Mar 14;8(11):18337-18347
pubmed: 28407691
Blood. 2005 Jan 15;105(2):481-8
pubmed: 15213095
Leukemia. 2017 Aug;31(8):1671-1677
pubmed: 28502982
Nat Biotechnol. 2007 Sep;25(9):1045-50
pubmed: 17704765
Development. 2009 Oct;136(20):3413-21
pubmed: 19762426
J Clin Oncol. 2003 Dec 15;21(24):4642-9
pubmed: 14673054
Clin Epigenetics. 2018 Apr 10;10:47
pubmed: 29643943
Circ Res. 2017 Jan 6;120(1):166-178
pubmed: 28057792
Leukemia. 2017 Dec;31(12):2543-2551
pubmed: 28400619
Oncogene. 2005 Jun 23;24(27):4472-6
pubmed: 15806146
Blood Adv. 2018 Jan 23;2(2):151-163
pubmed: 29365324
Nature. 2013 Aug 15;500(7462):345-9
pubmed: 23863936
Hum Mol Genet. 2000 Sep 1;9(14):2183-7
pubmed: 10958657
Nat Genet. 2008 Feb;40(2):237-42
pubmed: 18176563
Cancer Res. 1964 Oct;24:1544-51
pubmed: 14234000
Stem Cell Reports. 2017 Dec 12;9(6):2081-2096
pubmed: 29129685