Epigenetic silencing of long non-coding RNA BM742401 in multiple myeloma: impact on prognosis and myeloma dissemination
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PRIMARY RESEARCH
Cancer Cell International Open Access
Epigenetic silencing of long non‑coding RNA BM742401 in multiple myeloma: impact on prognosis and myeloma dissemination Zhenhai Li1,2, Shaji Kumar3, Dong‑Yan Jin4, George A. Calin5, Wee‑Joo Chng6, Kam‑Leung Siu4, Ming‑Wai Poon2 and Chor Sang Chim2*
Abstract Background: 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. Methods: Methylation-specific PCR and quantitative bisulfite pyrosequencing were performed to detect the meth‑ ylation 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. Results: BM742401 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. Conclusions: This 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. Keywords: Multiple myeloma, BM742401, DNA methylation, Overall survival Background Multiple myeloma is one form of hematological malignancy characterized by the accumulation and patchy infiltration of the bone marrow by neoplastic plasma cells, which accounts for approximately 10% of all *Correspondence: [email protected] 2 Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong, China Full list of author information is available at the end of the article
hematologic malignancies [1]. Active multiple myeloma is characterized by ≥ 10% clonal plasma cells in the bone marrow in addition to the presence of endorgan damages, including hypercalcemia, renal failure, anemia, and/or lytic bone lesions, which are collectively known as CRAB features [2]. Multiple myeloma is often preceded by an entirely asymptomatic state, monoclonal gammopathy of undetermined significance (MGUS), that progresses into symptomatic myeloma at
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