Epigenetic alterations and microRNAs

Figures & data

Table 1. The effect of gene methylation in MDS

Gene	Alteration	Result	Reference
p15INK4B	hypermethylation	Inactivation	9,10
WNT pathway	hypermethylation	inactivation	11
MAPK pathway	hypermethylation	inactivation	11
CDKN2A	hypermethylation	inactivation	11
CDKN2B	hypermethylation	inactivation	12
DOCK4	hypermethylation	Invasion of cancer cells	13
SOX7	hypermethylation	No inhibition of WNT pathway	14
Dab2	hypermethylation	Advanced MDS	15
DNMT3A	Somatic mutations (missence, nonsence, frameshift)	Aberrant DNA methylation	16,17
TET-2	Somatic mutations (missence, nonsence, frameshift)	DNA hypomethylation	18
IDH	Heterozygous mutations	Poor-prognosis MDS	37-40

Table 2. Histone modification in MDS

Gene	Alteration	Result	Reference
EZH2	Loss of function mutations (missence, donor-splice-site, frameshift)	Oncogenesis, ↓overall survival	45,47-49
SUZ1,2 EED	Mutations	Compromised PCR2 function	50 51
ASXL1	Loss of function mutations	Compromised PCR2 function	53
BMI1	Mutations	Poor prognosis MDS	56,57

Table 3. Downregulated microRNAs in MDS patients

microRNA	MDS subtype	Method	Reference
miR-10b, miR-103, miR-126, miR-140, miR-150, miR-342, miR-365, miR-378, miR-483, miR-558, miR-632, miR-636, miR-639	Low risk MDS	Agilent miRNA microarray and RT-PCR	76
miR-128b, miR-213, miR-95, miR-520c	5q- syndrome	Taqman miRNA microarray and RT-PCR	77
miR-221	sAML	RT-PCR	78
miR-196a*, miR-423–5p, miR-525–5p, miR-507, miR-583, miR-940, miR-1284, miR-1305, HS_122.1	All subtypes	Illumina miRNA microarray	79
miR-124, miR-206, miR-146a, miR-150, miR326, let-7e, mir-197, mir-875–5p	All subtypes	miRNA microarray-OSU3 and RT-PCR	85

Table 4. Upregulated microRNAs in MDS

microRNAs	MDS subtype	Method	Reference
miR-17–3p, miR-17–5p, miR-18a, miR-10a, miR-10b, miR-15a, miR-16, miR-222, miR-155, miR-181a, miR-21, miR-126	All subtypes	RT-PCR	80
miR-10a, miR-10b, miR-125a, miR-126, miR-130a, miR-148a, miR-151, miR-199a, miR-199b, miR-24, miR-29c, miR-335, miR-34a, miR-486, miR-99b	5q- syndrome	Taqman microRNA microarray and RT-PCR	77
miR-21	RCMD and RAEB	RT-PCR	81
miR-150	MDS-del(5q), MDS with low risk karyotype	RT-PCR	78
miR-299–3p, miR-299–5p, miR-323–3p, miR-329, miR-370, miR-409–3p, miR-431, miR-432, miR-494, miR-654–5p, miR-665, HS_40, HS_206	All subtypes	Illumina array	79
miR-222, miR-10a, miR-196a, miR-320, miR-100	All subtypes	miRNA microarray-OSU3 and RT-PCR	85

Figure 1. Epigenetic alteration of microRNAs and MDS pathogenesis Mir-124, which is hypermethylated and under-expressed in MDS patients, participates in MDS pathogenesis. It down-regulates the cyclin dependent kinase 6 (CDK6), which in turn phosphorylates and inactivates the tumor-suppressor protein Rb. EVI1 represses miR-124 expression by promoter methylation. It also down-regulates the expression of SMAD3, a member of TGF-β pathway that regulates cell differentiation, proliferation and apoptosis. Mir-124 activity can be restored by the treatment with the DNA methylation inhibitor, Decitabine. The TGF-β pathway is also regulated by mir-21 which down-regulates the expression of SMAD7, which in turn is a negative regulator of TGF-β receptor.

Aggerholm A, Holm MS, Guldberg P, Olesen LH, Hokland P. Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients. Eur J Haematol 2006; 76:23 - 32; http://dx.doi.org/10.1111/j.1600-0609.2005.00559.x; PMID: 16343268

 PubMed Web of Science ®Google Scholar

Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia: official journal of the Leukemia Society of America. Leukemia Research Fund, UK 2003; 17:1813 - 9; http://dx.doi.org/10.1038/sj.leu.2403054

 PubMed Web of Science ®Google Scholar

Figueroa ME, Skrabanek L, Li Y, Jiemjit A, Fandy TE, Paietta E, et al. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation. Blood 2009; 114:3448 - 58; http://dx.doi.org/10.1182/blood-2009-01-200519; PMID: 19652201

 PubMed Web of Science ®Google Scholar

Cechova H, Lassuthova P, Novakova L, Belickova M, Stemberkova R, Jencik J, et al. Monitoring of methylation changes in 9p21 region in patients with myelodysplastic syndromes and acute myeloid leukemia. Neoplasma 2012; 59:168 - 74; http://dx.doi.org/10.4149/neo_2012_022; PMID: 22248274

 PubMed Web of Science ®Google Scholar

Zhou L, Opalinska J, Sohal D, Yu Y, Mo Y, Bhagat T, et al. Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q. J Biol Chem 2011; 286:25211 - 23; http://dx.doi.org/10.1074/jbc.M111.235028; PMID: 21532034

 PubMed Web of Science ®Google Scholar

Fan R, Zhang LY, Wang H, Yang B, Han T, Zhao XL, et al. Methylation of the CpG island near SOX7 gene promoter is correlated with the poor prognosis of patients with myelodysplastic syndrome. Tohoku J Exp Med 2012; 227:119 - 28; http://dx.doi.org/10.1620/tjem.227.119; PMID: 22706399

 PubMed Web of Science ®Google Scholar

Yang Y, Zhang Q, Xu F, Chang C, Li X. Aberrant promoter methylation of Dab2 gene in myelodysplastic syndrome. Eur J Haematol 2012; 89:469 - 77; http://dx.doi.org/10.1111/ejh.12014; PMID: 23005040

 PubMed Web of Science ®Google Scholar

Ewalt M, Galili NG, Mumtaz M, Churchill M, Rivera S, Borot F, et al. DNMT3a mutations in high-risk myelodysplastic syndrome parallel those found in acute myeloid leukemia. Blood Cancer J 2011; 1:e9; http://dx.doi.org/10.1038/bcj.2011.7; PMID: 22829128

 PubMedGoogle Scholar

Walter MJ, Ding L, Shen D, Shao J, Grillot M, McLellan M, et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia: official journal of the Leukemia Society of America. Leukemia Research Fund, UK 2011; 25:1153 - 8; http://dx.doi.org/10.1038/leu.2011.44

 PubMed Web of Science ®Google Scholar

Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M, Huh J, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood 2009; 113:6403 - 10; http://dx.doi.org/10.1182/blood-2009-02-205690; PMID: 19372255

 PubMed Web of Science ®Google Scholar

Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462:739 - 44; http://dx.doi.org/10.1038/nature08617; PMID: 19935646

 PubMed Web of Science ®Google Scholar

Yoshida K, Sanada M, Kato M, Kawahata R, Matsubara A, Takita J, et al. A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders. Leukemia: official journal of the Leukemia Society of America. Leukemia Research Fund, UK 2011; 25:184 - 6; http://dx.doi.org/10.1038/leu.2010.241

 PubMed Web of Science ®Google Scholar

Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010; 42:722 - 6; http://dx.doi.org/10.1038/ng.621; PMID: 20601953

 PubMed Web of Science ®Google Scholar

Makishima H, Jankowska AM, Tiu RV, Szpurka H, Sugimoto Y, Hu Z, et al. Novel homo- and hemizygous mutations in EZH2 in myeloid malignancies. Leukemia: official journal of the Leukemia Society of America. Leukemia Research Fund, UK 2010; 24:1799 - 804; http://dx.doi.org/10.1038/leu.2010.167

 PubMed Web of Science ®Google Scholar

Herrera-Merchan A, Arranz L, Ligos JM, de Molina A, Dominguez O, Gonzalez S. Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. Nat Commun 2012; 3:623; http://dx.doi.org/10.1038/ncomms1623; PMID: 22233633

 PubMed Web of Science ®Google Scholar

Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 2004; 23:4061 - 71; http://dx.doi.org/10.1038/sj.emboj.7600402; PMID: 15385962

 PubMed Web of Science ®Google Scholar

Score J, Hidalgo-Curtis C, Jones AV, Winkelmann N, Skinner A, Ward D, et al. Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms. Blood 2012; 119:1208 - 13; http://dx.doi.org/10.1182/blood-2011-07-367243; PMID: 22053108

 PubMed Web of Science ®Google Scholar

Abdel-Wahab O, Adli M, LaFave LM, Gao J, Hricik T, Shih AH, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 2012; 22:180 - 93; http://dx.doi.org/10.1016/j.ccr.2012.06.032; PMID: 22897849

 PubMed Web of Science ®Google Scholar

Mihara K, Chowdhury M, Nakaju N, Hidani S, Ihara A, Hyodo H, et al. Bmi-1 is useful as a novel molecular marker for predicting progression of myelodysplastic syndrome and patient prognosis. Blood 2006; 107:305 - 8; http://dx.doi.org/10.1182/blood-2005-06-2393; PMID: 16160010

 PubMed Web of Science ®Google Scholar

Xu F, Yang R, Wu L, He Q, Zhang Z, Zhang Q, et al. Overexpression of BMI1 confers clonal cells resistance to apoptosis and contributes to adverse prognosis in myelodysplastic syndrome. Cancer Lett 2012; 317:33 - 40; http://dx.doi.org/10.1016/j.canlet.2011.11.012; PMID: 22120066

 PubMed Web of Science ®Google Scholar

Erdogan B, Facey C, Qualtieri J, Tedesco J, Rinker E, Isett RB, et al. Diagnostic microRNAs in myelodysplastic syndrome. Exp Hematol 2011; 39:915 - 26, e2; http://dx.doi.org/10.1016/j.exphem.2011.06.002; PMID: 21703983

 PubMed Web of Science ®Google Scholar

Votavova H, Grmanova M, Dostalova Merkerova M, Belickova M, Vasikova A, Neuwirtova R, et al. Differential expression of microRNAs in CD34+ cells of 5q- syndrome. J Hematol Oncol 2011; 4:1; http://dx.doi.org/10.1186/1756-8722-4-1; PMID: 21211043

 PubMed Web of Science ®Google Scholar

Hussein K, Theophile K, Büsche G, Schlegelberger B, Göhring G, Kreipe H, et al. Significant inverse correlation of microRNA-150/MYB and microRNA-222/p27 in myelodysplastic syndrome. Leuk Res 2010; 34:328 - 34; http://dx.doi.org/10.1016/j.leukres.2009.06.014; PMID: 19615744

 PubMed Web of Science ®Google Scholar

Dostalova Merkerova M, Krejcik Z, Votavova H, Belickova M, Vasikova A, Cermak J. Distinctive microRNA expression profiles in CD34+ bone marrow cells from patients with myelodysplastic syndrome. Eur J Hum Genet 2011; 19:313 - 9; http://dx.doi.org/10.1038/ejhg.2010.209; PMID: 21150891

 PubMed Web of Science ®Google Scholar

Sokol L, Caceres G, Volinia S, Alder H, Nuovo GJ, Liu CG, et al. Identification of a risk dependent microRNA expression signature in myelodysplastic syndromes. Br J Haematol 2011; 153:24 - 32; http://dx.doi.org/10.1111/j.1365-2141.2011.08581.x; PMID: 21332710

 PubMed Web of Science ®Google Scholar

Pons A, Nomdedeu B, Navarro A, Gaya A, Gel B, Diaz T, et al. Hematopoiesis-related microRNA expression in myelodysplastic syndromes. Leuk Lymphoma 2009; 50:1854 - 9; http://dx.doi.org/10.3109/10428190903147645; PMID: 19883312

 PubMed Web of Science ®Google Scholar

Bhagat TD, Zhou L, Sokol L, Kessel R, Caceres G, Gundabolu K, et al. miR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling. Blood 2013; 121:2875 - 81; http://dx.doi.org/10.1182/blood-2011-12-397067; PMID: 23390194

 PubMed Web of Science ®Google Scholar