Epigenetic inactivation of the hsa-miR-203 in haematological malignancies

Abstract

miR-203is a tumour suppressor microRNA (miRNA). We studied the methylation ofhsa-miR-203in 150 samples including acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL) and non-Hodgkin's lymphoma (NHL) by methylation-specific PCR, and miRNA expression by stem-loop RT-qPCR.hsa-miR-203promoter was unmethylated in normal controls but homozygously methylated in two AML and four lymphoma cell lines, in which 5-Aza-2′-deoxycytidine treatment led to promoter demethylation andmiR-203re-expression. Restoration ofmiR-203expression in lymphoma cells inhibited cellular proliferation and increased cell death, suggesting an inherent tumour suppressor activity. In primary samples,hsa-miR-203methylation was absent in CML but detected in 5.0% ALL, 10.0% AML, 42.0% CLL and 38.8% of NHL (including six [60.0%] natural killer-cell, nine [40.9%] B-cell and four [23.5%] T cell NHL). Moreover,hsa-miR-203methylation was associated with hypermethylation ofhsa-miR-34a, -124aand-196bin NHL but not CLL. In CLL,hsa-miR-203methylation was associated with a higher presenting Hb level (P= 0.033). The projected 10 year overall survival of the CLL patients was 58.2%, which was impacted by Rai stage and high-risk karyotypes but nothsa-miR-203methylation.hsa-miR-203was more frequently methylated in lymphoid than myeloid malignancies (P= 0.002). In conclusion,miR-203,a tumour suppressor gene, was hypermethylated in a tumour-specific manner with gene silencing.hsa-miR-203was more frequently hypermethylated in lymphoid than myeloid malignancies. In NHL,hsa-miR-203methylation was associated with concomitant methylation of other tumour suppressor miRNAs. The frequenthsa-miR-203methylation in lymphoid malignancies suggested a pathogenetic role ofhsa-miR-203methylation. © 2011 The Authors © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.