Abstract
miR-124-1 is a tumour suppressor microRNA (miR). Epigenetic deregulation of miRs is implicated in carcinogenesis. Promoter DNA methylation and histone modification of miR-124-1 was studied in 5 normal marrow controls, 4 lymphoma, 8 multiple myeloma (MM) cell lines, 230 diagnostic primary samples of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), MM, and non-Hodgkin's lymphoma (NHL), and 53 MM samples at stable disease or relapse. Promoter of miR-124-1 was unmethylated in normal controls but homozygously methylated in 4 of 4 lymphoma and 4 of 8 myeloma cell lines. Treatment of 5-Aza-2′-deoxycytidine led to miR-124-1 demethylation and re-expression of mature miR-124, which also associated with emergence of euchromatic trimethyl H3K4 and consequent downregulation of CDK6 in myeloma cells harboring homozygous miR-124-1 methylation. In primary samples at diagnosis, miR-124-1 methylation was absent in CML but detected in 2% each of MM at diagnosis and relapse/progression, 5% ALL, 15% AML, 14% CLL and 58.1% of NHL (p<0.001). Amongst lymphoid malignancies, miR-124-1 was preferentially methylated in NHL than MM, CLL or ALL. In primary lymphoma samples, miR-124-1 was preferentially hypermethylated in B- or NK/T-cell lymphomas and associated with reduced miR-124 expression. In conclusion, miR-124-1 was hypermethylated in a tumour-specific manner, with a heterochromatic histone configuration. Hypomethylation led to partial restoration of euchromatic histone code and miR re-expression. Infrequent miR-124-1 methylation detected in diagnostic and relapse MM samples showed an unimportant role in MM pathogenesis, despite frequent methylation found in cell lines. Amongst haematological cancers, miR-124-1 was more frequently hypermethylated in NHL, and hence warrants further study.
Highlights
DNA methylation involves the addition of a methyl group to the number 5 carbon of the cytosine ring in the CpG dinucleotide, by catalyzing the cytosine into methylcytosine through DNA methyltransferase [1,2]
We aimed to study the role of miR-124-1 methylation in a wide range of haematological malignancies including acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), multiple myeloma (MM) and nonHodgkin’s lymphoma (NHL)
In this study, we showed that miR-124-1 is not methylated in normal blood cells but is hypermethylated in lymphoma and myeloma cell lines, which can be re-expressed upon hypomethylating treatment
Summary
DNA methylation involves the addition of a methyl group to the number 5 carbon of the cytosine ring in the CpG dinucleotide, by catalyzing the cytosine into methylcytosine through DNA methyltransferase [1,2]. Cancer cells are characterized by global DNA hypomethylation but gene-specific hypermethylation of promoterassociated CpG islands of tumour suppressor genes (TSGs), resulting in transcriptional repression, and serve as an alternative mechanism of gene inactivation. Based on a pathwayspecific approach, multiple TSGs across pathways including cell cycle regulation, JAK/STAT signalling, WNT signalling, and DAP kinase-associated intrinsic tumour suppression have been shown to be inactivated by gene hypermethylation in leukaemia, lymphoma and multiple myeloma [3,4,5,6,7,8,9,10,11]. MiR-124-1 has been shown to downregulate CDK6 translation by binding on the 39 untranslated region (39 UTR) of the CDK6 mRNA, and reduce the retinoblastoma protein phosphorylation, thereby demonstrating the tumour suppressor role of miR-124-1 [14]
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