DNA Methylation Events as Markers for Diagnosis and Management of Acute Myeloid Leukemia and Myelodysplastic Syndrome

Table 1

Methylated genes as markers for AML or MDS.

Gene	Disease	Patients (n)	Sample type	Associated factors	Ref.
AWT1	AML	356	BM/B	Classification of myeloid-derived leukemias. Hypermethylation could monitor the recurrence of disease during remission in patients undergoing allogeneic stem cell transfer.	[79]
BMI1	AML/MDS	54	BM/B	DNA methylation was associated with poor prognosis.	[80]
C1R	AML	194	B	DNA methylation was associated with the occurrence of specific genomic mutations that are used for risk stratification.	[76]
CDH	MDS	60	BM	DNA methylation was associated with poor prognosis and lower complete remission.	[81]
CDH1	MDS	317	BM/B	Aberrant DNA methylation predicts overall survival and progression-free survival.	[82]
CDH1	MDS	37	BM	Hypermethylation can contribute to the development and poor outcome of disease.	[83]
CDH13	MDS	317	BM/B	Aberrant DNA methylation predicts overall survival and progression-free survival.	[82]
CDKN2B	MDS	78	BM	DNA methylation was associated with leukemic transformation and disease progression.	[84]
CDKN2B	MDS	25	BM	DNA methylation was associated with pathogenesis and prognosis.	[85]
CEBPA	AML	181	BM	Methylation was associated with better outcome.	[86]
CXXC5	AML	529	BM	Gene was associated with tumor suppressor function in AML and better outcome.	[87]
DLC-1	MDS	43	BM/B	DNA methylation was associated with poor prognosis.	[88]
DLX4	MDS	103	BM	DNA methylation was associated with poor outcome and shorter overall survival	[72]
DNMT3A	LMA	88	B	Methylation was associated with poor prognosis.	[89]
ERalpha-A	Leukemia cases with ERalpha-A methylation (95%; 38 of 40)	40	B	Patients with ERalpha-A methylation had no symptomatic relief and patients without this methylation obtained effective relief. ERalpha-A plays a significant role in leukemogenesis.	[90]
ERalpha-A	MDS	317	BM/B	Aberrant DNA methylation predicts overall survival and progression-free survival.	[82]
ERalpha-A	MDS	37	BM	Hypermethylation can contribute to the development and poor outcome of disease.	[83]
EVI1	LMA	476	BM/B	Hipomethylation was associated with poor prognosis.	[91]
EZH2	AML/MDS	54	BM/B	DNA methylation was associated with poor prognosis.	[80]
FHIT	MDS	—	B	DNA methylation was associated with pathogenesis.	[92]
GPX3	MDS	110	BM	DNA methylation was associated with poor prognosis and progression to leukemia in MDS.	[73]
HIC1	MDS	37	BM	Hypermethylation can contribute to the development and poor outcome of disease.	[83]
HIC1	AML	378	BM/B	Hypermethylation was frequently observed in all types of leukemia and strongly correlated with progression to blast crisis.	[93]
HOXA5	AML	378	BM/B	Hypermethylation was frequently observed in all types of leukemia and strongly correlated with progression to blast crisis. Reexpression resulted in the induction of markers of granulocytic differentiation.	[93]
HRK	MDS	60	BM	DNA methylation was associated with advanced stage of MDS and progression.	[94]
ID4	LMA	212	BM	DNA methylation was associated with shorter overall survival	[73]
ID4	MDS	142	BM	DNA methylation was suggested as biomarker for diagnosis.	[95]
ID4	MDS	100	BM	DNA methylation was suggested as biomarker for diagnosis.	[96]
ID4	AML	14	BM	DNA methylation was suggested as biomarker for minimal residual disease detection.	[66]
LET-7A-3	MDS	95	BM	DNA methylation was associated with poor prognosis.	[97]
MGMT	AML	21	BM/B	Co-methylation with p15 gene showed high proportion of leukemic blast cells.	[77]
MGMT	AML	30	BM	DNA methylation was suggested as biomarker to predict therapeutic outcome in male AML patients.	[98]
NOR1	MDS	317	BM/B	Aberrant DNA methylation predicts overall survival and progression-free survival.	[82]
NPM2	MDS	317	BM/B	Aberrant DNA methylation predicts overall survival and progression-free survival.	[82]
OLIG2	MDS	317	BM/B	Aberrant DNA methylation predicts overall survival and progression-free survival.	[82]
p15	AML	21	BM/B	DNA methylation was associated with higher frequency of early death. Comethylation with MGMT gene showed high proportion of leukemic blast cells.	[77]
p15^INK4b	MDS	53	BM	DNA methylation was associated with worse prognosis increasing with disease evolution to AML.	[99]
p15^INK4b	t-MDS; t-AML	81	BM/B	DNA methylation presented a significantly shorter survival and correlated with loss of chromosome arm 7q.	[100]
p15^INK4b	MDS	47	BM	DNA methylation was associated with pediatric disease evolution.	[101]
p15^INK4b	MDS	317	BM/B	Aberrant DNA methylation predicts overall survival and progression-free survival.	[83]
p15^INK4b	MDS	47	BM	DNA methylation was associated with pediatric disease evolution.	[102]
p21	MDS	88	BM	DNA methylation could predict clinical outcome.	[103]
p73	MDS	88	BM	DNA methylation was associated with poor prognosis in de novo MDS.	[103, 104]
PcG	AML	118	BM	DNA methylation was associated with poor prognosis.	[105]
PGRA	MDS	317	BM/B	Aberrant DNA methylation predicts overall survival and progression-free survival.	[82]
PGRB	MDS	317	BM/B	Aberrant DNA methylation predicts overall survival and progression-free survival.	[82]
PLA2R1	MDS	32	B	DNA methylation was associated with disease evolution in MDS and leukemogenesis	[106]
PLK	Onco-hematological diseases	ND	BM	Promoter methylation correlates with disease and tumorigenesis in blood neoplasms.	[107]
PPARD	AML	344	BM/B	DNA methylation was associated with favorable outcome.	[108]
PSMD2	AML	344	BM/B	DNA methylation was associated with favorable outcome.	[108]
RIL	MDS	317	BM/B	Aberrant DNA methylation predicts overall survival and progression-free survival.	[82]
RING1	AML/MDS	54	BM/B	DNA methylation was associated with poor prognosis.	[80]
sFRP1	MDS	144	BM	DNA methylation was associated with worse overall survival and poor prognosis	[74]
sFRP2	AML	72	BM/B	DNA methylation was associated with increased risk of relapse and risk of death, predicting adverse clinical outcome in patients with normal karyotypes.	[109]
sFRP2	MDS	144	BM	DNA methylation was associated with worse overall survival and poor prognosis	[74]
sFRP5	AML	72	BM/B	DNA methylation was associated with increased risk of relapse and risk of death, predicting adverse clinical outcome in patients with normal karyotypes.	[109]
sFRP5	MDS	144	BM	DNA methylation was associated with worse overall survival and poor prognosis	[74]
SOCS-1	MDS	100	B	DNA methylation was associated with disease progression and poor survival	[75]
SOX17	MDS	164	BM	DNA methylation was associated with poor prognosis.	[110]
TERTpro/Ex1	AML	43	BM	Hypermethylation was associated with inferior patient survival.	[111]
TERTpro/Ex1	AML/MDS	33	BM/B	DNA methylation was associated with poor prognosis and inferior patient survival.	[111]
VTRNA1–3	MDS	140	BM	DNA methylation was associated with poor outcome.	[112]
XPNPEP	AML	344	BM/B	DNA methylation was associated with unfavorable outcome.	[108]
ZO-1	MDS	ND	BM	DNA methylation was associated with disease progression.	[113]

AML: acute myeloid leukemia; B: peripheral blood; BM: bone marrow; MDS: myelodysplastic syndrome; ND: not declared; t-AML: therapy-related acute myeloid leukemia; t-MDS: therapy-related myelodysplastic syndrome.