EWSR1 overexpression is a pro-oncogenic event in multiple myeloma
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ORIGINAL ARTICLE
EWSR1 overexpression is a pro‑oncogenic event in multiple myeloma Daichi Nishiyama1 · Yoshiaki Chinen1,2 · Reiko Isa1 · Yuto Fujibayashi1 · Saeko Kuwahara‑Ota1 · Junko Yamaguchi1 · Tomoko Takimoto‑Shimomura1 · Yayoi Matsumura‑Kimoto1 · Taku Tsukamoto1 · Yuji Shimura1 · Tsutomu Kobayashi1 · Shigeo Horiike1 · Masafumi Taniwaki3 · Hiroshi Handa4 · Junya Kuroda1 Received: 6 July 2020 / Revised: 3 October 2020 / Accepted: 5 October 2020 © Japanese Society of Hematology 2020
Abstract Multiple myeloma (MM) is cytogenetically, genetically and molecularly heterogenous even among subclones in one patient, therefore, it is essential to identify both frequent and patient-specific drivers of molecular abnormality. Following previous molecular investigations, we in this study investigated the expression patterns and function of the Ewing sarcoma breakpoint region 1 (EWSR1) gene in MM. The EWSR1 transcriptional level in CD138-positive myeloma cells was higher in 36.4% of monoclonal gammopathy of undetermined significance, in 67.4% of MM patients compared with normal plasma cells, and significantly higher in ten human myeloma-derived cell lines (HMCLs) examined. EWSR1 gene knockdown caused growth inhibition with an increase of apoptotic cells in NCI-H929 and KMS-12-BM cells. Gene expression profiling using microarray analysis suggested EWSR1 gene knockdown caused transcriptional modulation of several genes associated with processes such as cell proliferation, cell motility, cell metabolism, and gene expression. Of particular, EWSR1 gene knockdown caused upregulation of let-7c and downregulation of its known targets K-RAS and AKT. Finally, our analysis using community database suggested that high EWSR1 expression positively associates with poor prognosis and advanced disease stage in MM. These findings suggest that EWSR1 overexpression is a pro-oncogenic molecular abnormality that may participate in MM progression. Keywords Multiple myeloma · EWSR1 · Cell proliferation · Cell motility · microRNA
Introduction Identification of a disease-specific molecule is required for development of a diagnostic biomarker for prediction of prognosis and efficacy of targeted therapy in cancer. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12185-020-03027-0) contains supplementary material, which is available to authorized users. * Junya Kuroda [email protected]‑m.ac.jp 1
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii‑cho, Kamigyo‑ku, Kyoto 602‑8566, Japan
2
Department of Hematology, Fukuchiyama City Hospital, Fukuchiyama, Japan
3
Center for Molecular Diagnostics and Therapeutics, Kyoto Prefectural Univesity of Medicine, Kyoto, Japan
4
Department of Hematology, Gunma University Graduate School of Medicine, Maebashi, Japan
Multiple myeloma (MM) is the major clinicopathological category of plasma cell dyscrasias and the second most common hematologic malignancy. Development and progression of MM a
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