Unravelling the Epigenome of Myelodysplastic Syndrome: Diagnosis, Prognosis, and Response to Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. MDS Diagnosis and Prognosis
3. Treatment Options for MDS
4. MDS Pathophysiology
5. Epigenetic Modifiers
5.1. DNA Methylation
5.2. Non-Coding RNAs
5.2.1. Micro-RNAs
5.2.2. Long Non-Coding RNAs
6. Epigenetic Modifiers That Aid in the Diagnosis of MDS
6.1. DNA Methylation as a Diagnostic Tool for MDS
6.2. miRNA and lncRNA Signatures for the Diagnosis of MDS
6.2.1. miRNAs
6.2.2. lncRNAs
7. Epigenetic Modifiers That Are Associated with MDS Prognosis
7.1. DNA Methylation Signatures That Predict Prognosis
7.2. miRNAs That Predict Prognosis
7.3. lncRNAs That Predict Prognosis
8. Epigenetic Modifiers as Biomarkers for Response to HMAs in MDS
8.1. DNA Methylation as a Biomarker for Treatment Response in MDS
8.2. ncRNAs as Biomarkers That Predict Response to HMA Therapy in MDS
9. Epigenetic Modifiers in the MDS Bone Marrow Micro-Environment (BMME)
9.1. DNA Methylation in BMME
9.2. miRNA and lncRNA in BMME
10. Epigenetic Modifiers in MDS: Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Epigenetic Modifier | Diagnosis |
---|---|
DNA Methylation | High global levels of methylation (5mC) in bone marrow cells in 85% of MDS cases [65] |
Hypermethylation at enhancers, particularly in patients with TET2 loss of function mutations [66,67] | |
Increased CpG promoter methylation: | |
Hypomethylation of let-7a-3 promoter in MDS vs. controls [78] | |
miRNA | Overexpression of DLK1-DIO3 region (large miRNA cluster and lncRNA MEG3 promoter) in 50% of high-risk MDS who progressed to AML with myelodysplasia [79] |
miRNA signature that discriminated MDS from healthy controls: miR-378, miR-632, miR-636 [80], let-7 family [81] | |
Higher percentage of miRNAs expressed in low-risk MDS compared to controls or high-risk MDS [82] | |
Increased expression of miR-34a, miR-125a and miR-150 and miRNAs clustered on 14q32 in MDS [83] | |
Increased expression in MDS: miR-17-92 cluster [84], miR-222, miR-10a [81], miR-194-5p, miR-320a [85], miR-21 [86,87], miR-34b [88], miR-661 [89], miR-720 [87], miR-205-5p [90] | |
Decreased expression: miR-124 [91], miR-146a, miR-150, let-7e [81], miR-143 [92], miR-671-5p, miR-BART13 [87], miR-155, miR-182, miR-124a, miR-200c, miR-342-5p and let-7a [93] | |
EV cargo from transfusion-dependent MDS cases – higher numbers of small RNAs and miRNAs, upregulated expression: miR-584J, miR-4485; down-regulation of: miR-28, let-7d [94] | |
21 exosomal miRNA signature strongly associated with MDS [95] | |
lncRNA | lncRNA (lncENST00000444102) and ABAT were significantly downregulated in MDS [96] |
Significantly decreased LEF1-AS1 in MDS [97] | |
linc-BDH1-1, linc-FAM75A7-7, linc-HHLA2-2, linc-JMJD1C-3, linc-PRKD1-2 and linc-RPIA aberrantly expressed in MDS [98] | |
High expression of TC07000551.hg.1, TC08000489.hg.1, TC02004770.hg.1, and TC03000701 in MDS [99] | |
Overexpression of CCAT2 [100] | |
Novel lncRNA LOC101928834 upregulated in MDS bone marrow cells, could discriminate MDS-RAEB patients from controls (AUC 0.9048) [101] | |
590 downregulated lncRNAs and 372 upregulated lncRNAs in MDS; co-ordinated and abnormal lncRNA and mRNA transcriptomes [102] |
Epigenetic Modifier | Prognosis |
---|---|
DNA Methylation | High global DNA methylation levels → decreased OS and increased progression to AML [108,109] |
MDS patients grouped based on DNA methylation profiles correlates with OS [110] | |
Hypomethylation of CD93 → shorter OS [110] | |
Hypermethylation of a 10 gene signature (CDH1, CH13, ER-alpha, NOR1, NPM2, OLIG2, p15INK4B, PGRA, PGRB and RIL) → shorter OS and PFS [112] | |
SOX7 [70], GPX3 [74], SOCS1, CDKN2B [113], miR-124 [91], DLX4 [73], DLX5 [114], sFRP1/4/5 [77], p73 [115], VTRNA1-3 [116] and ABAT [69] promoter methylation → decreased OS and increased progression to AML | |
Hypermethylation of p15INK4B, HIC1, CDH1, and ER → poor prognosis [117] | |
Hypermethylation of CDKN2B associated with disease progression and leukemic transformation [76] | |
High methylation index (promoter and gene body methylation) → very high risk MDS [118] | |
SHP-1 promoter hypermethylation → high-risk MDS [120] | |
FOXO3 and CHEK2 promoter methylation → high risk indicators [119] | |
Increased methylation of DLC-1 in high-risk MDS vs. low-risk MDS [75] | |
Methylation of HRK [121] and SOX17 [72] → advanced stage and high-risk MDS | |
MEG3 hypermethylation (in 50% of patients) → longer PFS [79] | |
Hypomethylation of DNMT3A (57% of patients) [111] and let-7a-3 (23.2% of patients) [78] → shorter OS | |
miRNA | 10 miRNA signature (miR-181a/b/c/d, miR-221, miR-376b, miR-125b, miR-155, miR-130a and miR-486-5p) discriminated between low and high-risk MDS [81] |
High miR-15a (BM) and low miR-16 (PB) in high-risk MDS [84] | |
Increased miR-181 family expression → Higher-risk MDS and progression to AML [81] | |
5 miRNAs (miR-4865p, miR-181a-5p, miR-181b-5p, miR-199b-5p, miR-181d-5p) predicted progression to AML [122] | |
Decreased expression of miR-17-5p and miR-20a, let-7a → High-risk MDS [123] | |
Lower expression of miR-21, miR-126, miR-146b-5p, miR-155 in low-risk vs. high-risk MDS [93] | |
High expression of miR-126, miR-155 and miR-124a [93], miR-661 [89], miR-100-5p [124], miR-194-5p, miR-320a [85], miR-181 family [81,84], miR-125a, miR-99b [125] and miR-22 [126] → poor survival | |
Low expression of miR-194-5p → poor OS [85] | |
Low expression of miR-126* → shorter OS, PFS and increased relapse [127] | |
High expression of miR-17-5p and miR-20a → increased OS / good prognosis [123] | |
Decreased circulating levels of miR-27a-3p, miR-150-5p, miR-199a-5p, miR-223-3p and miR-451a → High risk MDS and poor prognosis [128] | |
High plasma miR-451a → independent predictor of longer PFSHigh plasma miR-223-3p levels significantly associated with better OS [128] | |
High circulating Let-7a and miR-16 levels → poor PFS and OS [129] Plasma 7 miRNA signature (high let-7a, miR-144, miR-16, miR-25, miR-451 and low miR-651, miR-655; 75% accuracy) → poor survival [130] | |
lncRNA | Overexpression if MEG3 (50% of patients) → poor prognosis [79] |
Overexpression of HOXB-AS3 → shorter OS, poor prognosis for low-risk MDS [131] | |
High LOC101928834 expression [101] and high serum KCNQ1OT1 expression [132] → poor survival | |
High lncRNA score (TC07000551.hg.1, TC08000489.hg.1, TC02004770.hg.1, and TC03000701.hg.1) → poor OS and likely to progress to leukemia [99] |
Epigenetic Modifier | Treatment Response |
---|---|
DNA Methylation | DNMT3A, TET2 [136,137], IDH1, IDH2 mutations → better response to HMAs [133,134] |
Loss of methylation during treatment → better response to HMAs [112] | |
AZA responders showed stable global methylation levels before and after treatment [138] | |
Hypermethylation of EZH2 (promoter) and NOTCH1 (intragenic) before treatment and hypomethylation after treatment → best cytological response to AZA [138] | |
Hypermethylation of CDA [139], CDKN2B [144] or PLCB1 [140,141,142,143] before treatment → better response to HMAs | |
Reduced DLC-1 methylation after AZA → better response to AZA [147] | |
Better recovery of methylation at time of next course of AZA → better response to AZA [118] | |
Increased 5-AZA-CdR incorporation into DNA [148] and less AZA incorporation into RNA [149] → better response to AZA | |
miRNA | Low serum expression of miR-21 before treatment → better response to HMAs and PFS [150] |
Decreased expression of miR-100-5p and miR-133b, and increased miR-17-3p in MDS BM cells → predict better ORR [124] | |
Plasma miRNA signature (miR-423-5p, miR-126-3p, miR-151a-3p, miR-125a-5p, miR-199a-3p) → predict response to AZA [83] | |
Low expression of miR-126* → lower response rate, higher relapse rate, shorter PFS and OS [127] | |
lncRNA | Upregulation of PU.1 an JPD2 expression → better clinical response to AZA [151] |
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Bond, D.R.; Lee, H.J.; Enjeti, A.K. Unravelling the Epigenome of Myelodysplastic Syndrome: Diagnosis, Prognosis, and Response to Therapy. Cancers 2020, 12, 3128. https://doi.org/10.3390/cancers12113128
Bond DR, Lee HJ, Enjeti AK. Unravelling the Epigenome of Myelodysplastic Syndrome: Diagnosis, Prognosis, and Response to Therapy. Cancers. 2020; 12(11):3128. https://doi.org/10.3390/cancers12113128
Chicago/Turabian StyleBond, Danielle R., Heather J. Lee, and Anoop K. Enjeti. 2020. "Unravelling the Epigenome of Myelodysplastic Syndrome: Diagnosis, Prognosis, and Response to Therapy" Cancers 12, no. 11: 3128. https://doi.org/10.3390/cancers12113128