Abstract
BM742401 is a tumor suppressor lncRNA downregulated in gastric cancer. As the promoter region and the entire transcript are embedded in a CpG island, we postulated that BM742401 is a tumor suppressor lncRNA inactivated by DNA methylation in chronic lymphocytic leukemia (CLL). The promoter of BM742401 was unmethylated in normal controls including three each of normal bone marrow, peripheral blood buffy coats, and CD19-sorted peripheral B-cells, but methylated in four (57.1%) CLL cell lines. Methylation of BM742401 correlated inversely with expression. In the completely methylated WAC3CD5+ CLL cells, 5-Aza-2′-deoxycytidine treatment led to promoter demethylation and re-expression of BM742401 transcript. Functionally, stable overexpression of BM742401 resulted in inhibition of cellular proliferation and enhanced apoptosis through caspase-9-dependent intrinsic but not caspase-8-dependent extrinsic apoptosis pathway, suggesting a tumor suppressor role of BM742401 in CLL. In primary CLL samples, methylation of BM742401 was detected in 43/98 (43.9%) of patients. Moreover, among CLL patients with standard-risk cytogenetic aberrations, methylation of BM742401 correlated with advanced Rai stage (≥ stage 2)(P = 0.002). Furthermore, BM742401 methylation was associated with miR-129-2 methylation (P = 0.05). BM742401 is a tumor suppressor lncRNA frequently methylated in CLL. The mechanism of BM742401 as a tumor suppressor warrants further studies.
Highlights
DNA methylation refers to the addition of a methyl group (−CH3) to the carbon 5 position of the cytosine ring in a CpG dinucleotide, leading to the formation of 5-methylcytosine [1]
chronic lymphocytic leukemia (CLL) cell lines In CLL cell lines, M-/Methylation-specific polymerase chain reaction (MSP) for the unmethylated allele (U-MSP) analysis showed that the promoter of BM742401 was completely methylated (MM) in MEC1, I83-E95 and WAC3CD5+, partially methylated (MU) in HG3, and completely unmethylated (UU) in MEC2, 232B4, and CLL-AAT (Figure 1C)
BM742401 expression in CLL cell lines inversely correlated with methylation status
Summary
DNA methylation refers to the addition of a methyl group (−CH3) to the carbon 5 position of the cytosine ring in a CpG dinucleotide, leading to the formation of 5-methylcytosine [1]. Methylation-mediated silencing of both protein-coding TSGs, including DAPK1, ID4 and SFRP1, and tumor suppressor miRNAs, including miR-9-3, miR-34b/c, miR-129-2, miR-203 and miR-3151, have been implicated in CLL leukemogenesis or prognosis [7,8,9,10,11,12,13]. Long non-coding RNA (lncRNA) is defined as a novel class of RNAs longer than 200 nucleotides with little or no protein-coding capacity. It can be further be categorized into five subgroups, including intergenic, intragenic, natural antisense transcripts, pseudogenes and unclassified transcripts, based on the location relative to annotated protein-coding genes (PCGs) [14, 15]. LncRNAs are known to activate or inhibit gene expression involved in multiple biological processes through epigenetic, transcriptional or post-transcriptional mechanisms [16, 17]
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