Abstract
BackgroundLong non-coding RNA (lncRNA) BM742401 is a tumor suppressor in gastric cancer and chronic lymphocytic leukemia. As the promoter and coding region of BM742401 are fully embedded in a CpG island, we hypothesized that BM742401 is a tumor suppressor lncRNA epigenetically silenced by promoter DNA methylation in multiple myeloma.MethodsMethylation-specific PCR and quantitative bisulfite pyrosequencing were performed to detect the methylation of BM742401 in normal plasma cells, myeloma cell lines and primary myeloma samples. The expression of BM742401 was measured by qRT-PCR. The function of BM742401 in multiple myeloma cells was analyzed by lentivirus transduction followed by migration assay.ResultsBM742401 methylation was detected in 10 (66.7%) myeloma cell lines but not normal plasma cells, and inversely correlated with expression of BM742401. In primary samples, BM742401 methylation was detected in 3 (12.5%) monoclonal gammopathy of undetermined significance, 9 (15.8%) myeloma at diagnosis and 8 (17.0%) myeloma at relapse/progression. Moreover, BM742401 methylation at diagnosis was associated with inferior overall survival (median OS: 25 vs. 39 months; P = 0.0496). In myeloma cell line JJN-3, stable overexpression of BM742401 by lentivirus transduction resulted in reduced cell migration (P = 0.0001) but not impacting cell death or proliferation.ConclusionsThis is the first report of tumor-specific methylation-mediated silencing of BM742401 in myeloma, which is likely an early event in myelomagenesis with adverse impact on overall survival. Moreover, BM742401 is a tumor suppressor lncRNA by inhibiting myeloma cell migration, hence implicated in myeloma plasma cell homing, metastasis and disease progression.
Highlights
Long non-coding RNA BM742401 is a tumor suppressor in gastric cancer and chronic lym‐ phocytic leukemia
As the promoter and coding region of BM742401 are fully embedded in a CpG island, we hypothesized that BM742401 may be a tumor suppressor Long non-coding RNA (lncRNA) epigenetically silenced by promoter DNA methylation in multiple myeloma
We studied the methylation status of BM742401 promoter in healthy controls, myeloma cell lines and myeloma primary samples, and investigated its tumor suppressor function
Summary
Long non-coding RNA (lncRNA) BM742401 is a tumor suppressor in gastric cancer and chronic lym‐ phocytic leukemia. As the promoter and coding region of BM742401 are fully embedded in a CpG island, we hypoth‐ esized that BM742401 is a tumor suppressor lncRNA epigenetically silenced by promoter DNA methylation in multiple myeloma. LncRNA CRNDE (colorectal neoplasia differentially expressed) was found to be upregulated in primary myeloma samples and cell lines as compared with healthy controls, and associated with poor OS, and knockdown of CRNDE inhibited myeloma cell proliferation and colony formation and increased apoptosis and cell cycle arrest in G0/G1 phase [13], suggesting an oncogenic role for CRNDE in myeloma. Knockdown of lncRNA OIP5-AS1 has been shown to promote myeloma cell proliferation, cell cycle progression and inhibit apoptosis, suggesting OIP5-AS1 is a tumor suppressor in myeloma [14]
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