Abstract
Promoter hypermethylation‐mediated inactivation of ID4 plays a crucial role in the development of solid tumours. This study aimed to investigate ID4 methylation and its clinical relevance in myeloid malignancies. ID4 hypermethylation was associated with higher IPSS scores, but was not an independent prognostic biomarker affecting overall survival (OS) in myelodysplastic syndrome (MDS). However, ID4 hypermethylation correlated with shorter OS and leukaemia‐free survival (LFS) time and acted as an independent risk factor affecting OS in acute myeloid leukaemia (AML). Moreover, ID4 methylation was significantly decreased in the follow‐up paired AML patients who achieved complete remission (CR) after induction therapy. Importantly, ID4 methylation was increased during MDS progression to AML and chronic phase (CP) progression to blast crisis (BC) in chronic myeloid leukaemia (CML). Epigenetic studies showed that ID4 methylation might be one of the mechanisms silencing ID4 expression in myeloid leukaemia. Functional studies in vitro showed that restoration of ID4 expression could inhibit cell proliferation and promote apoptosis in both K562 and HL60 cells. These findings indicate that ID4 acts as a tumour suppressor in myeloid malignancies, and ID4 methylation is a potential biomarker in predicting disease progression and treatment outcome.
Highlights
Myeloid malignancies are a clonal disease derived from myeloid haematopoietic stem/progenitor cells, which usually include myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)
We established K562 (Fig. 8A and B) and HL60 (Fig. 9A and B) cells overexpressing ID4 confirmed by RQ-PCR and Western blot
Increased ID4 methylation level was frequently occurred in patients with MDS, AML and blast crisis (BC)-CML
Summary
Myeloid malignancies are a clonal disease derived from myeloid haematopoietic stem/progenitor cells, which usually include MDS, AML and CML. MDS represents a diverse group of clonal haematopoietic disorders characterized by peripheral blood cytopenias, ineffective production of blood cells and high risks of transformation to AML [1]. Cytogenetic abnormalities and molecular biological changes including gene mutations and abnormal gene expression play vital roles in leukaemogenesis [3]. Approximately 45% of de novo AML is normal karyotypes, whose pathogenesis is complex and Epigenetics refers to variability in gene expression without any underlying modification in the actual genetic sequence, mainly including DNA methylation, histone modifications and microRNAs expression [7].
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