Abstract
BackgroundMyelodysplastic syndrome (MDS) eventually transforms into acute leukemia (AL) in about 30% of patients. Hypermethylation of the inhibitor of DNA binding 4 (ID4) gene may play an important role in the initiation and development of MDS and AL. The aim of this study was to quantitatively assess ID4 gene methylation in MDS and to establish if it could be an effective method of evaluating MDS disease progression.MethodsWe examined 142 bone marrow samples from MDS patients, healthy donors and MDS-AL patients using bisulfite sequencing PCR and quantitative real-time methylation-specific PCR. The ID4 methylation rates and levels were assessed.ResultsID4 methylation occurred in 27 patients (27/100). ID4 gene methylation was more frequent and at higher levels in patients with advanced disease stages and in high-risk subgroups according to WHO (P < 0.001, P < 0.001, respectively) and International Prognostic Scoring System (IPSS) (P = 0.002, P = 0.007, respectively) classifications. ID4 methylation levels changed during disease progression. Both methylation rates and methylation levels were significantly different between healthy donor, MDS patients and patients with MDS-AL (P < 0.001, P < 0.001, respectively). Multivariate analysis indicated that the level of ID4 methylation was an independent factor influencing overall survival. Patients with MDS showed decreased survival time with increased ID4 methylation levels (P = 0.011, hazard ratio (HR) = 2.371). Patients with ID4 methylation had shorter survival time than those without ID4 methylation (P = 0.008).ConclusionsOur findings suggest that ID4 gene methylation might be a new biomarker for MDS monitoring and the detection of minimal residual disease.
Highlights
Myelodysplastic syndrome (MDS) eventually transforms into acute leukemia (AL) in about 30% of patients
Samples for bisulfite sequencing study corresponded to bone marrow specimens from a healthy donor, bone marrow from a patient with MDS who was diagnosed with refractory anemia (MDS-RA) and bone marrow from a patient with acute myeloid leukemia (MDS-AML) (M6)
Comparison of inhibitor of DNA binding 4 (ID4) gene methylation status in normal bone marrow (NBM), MDS, and MDS-AL by methylight ID4 methylation positivity rates were different among the NBM (0%), patients with MDS (27%) and patients with MDS-AL (68.18%)
Summary
Myelodysplastic syndrome (MDS) eventually transforms into acute leukemia (AL) in about 30% of patients. MDS pathogenesis and its frequent progression to AL are associated with aberrant cell clones with little ability for differentiation but with a high ability to proliferate [5,6]. This aberration of MDS is believed to be a multistep process of aberrant expression of the tumor suppressor gene (TSG) requiring both aberrant genetic and. Previous studies have demonstrated that abnormal hypermethylation of many TSG promoter regions such as CpG islands are associated with MDS development and progression [12,13,14,15,16,17]. It is well known that with the development of MDS, there are increases in abnormal blasts in bone marrow, which may be the result of abnormal expression of TSG in terms of cell cycle, cell differentiation, and cell proliferation
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