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EWSR1 overexpression is a pro-oncogenic event in multiple myeloma

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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.

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Acknowledgements

We thank Ms. N. Sakamoto-Inada and Mr. N. Kawasumi for their excellent scientific support. The study was supported in part by National Cancer Center Research and Development Funds (26-A-4, 29-A-3), a Grant-in-Aid for Clinical Cancer Research (H26-kakushin-teki-gan-ippan-074) from the Ministry of Health, Labour and Welfare of Japan, by AMED (JP16ck0106077h003, JP17ck0106348h0001, JP18ck0106348h0002 and JP19ck0106348h0003) (JK), by Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology of Japan [MEXT KAKENHI 16K09856 (MT) and MEXT KAKENHI 18K08367 (TK)], and by a Japanese Society for Myeloma Research Award (YS).

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan

    Daichi Nishiyama, Yoshiaki Chinen, Reiko Isa, Yuto Fujibayashi, Saeko Kuwahara-Ota, Junko Yamaguchi, Tomoko Takimoto-Shimomura, Yayoi Matsumura-Kimoto, Taku Tsukamoto, Yuji Shimura, Tsutomu Kobayashi, Shigeo Horiike & Junya Kuroda

  2. Department of Hematology, Fukuchiyama City Hospital, Fukuchiyama, Japan

    Yoshiaki Chinen

  3. Center for Molecular Diagnostics and Therapeutics, Kyoto Prefectural Univesity of Medicine, Kyoto, Japan

    Masafumi Taniwaki

  4. Department of Hematology, Gunma University Graduate School of Medicine, Maebashi, Japan

    Hiroshi Handa

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  1. Daichi Nishiyama
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  2. Yoshiaki Chinen
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Contributions

DN, YC, RI, YF, SK-O, JY, TT-S, YM–K, TT, YS, TK, SH, MT, HH and JK performed experiments and analyzed data. DN and JK drafted the manuscript. DN, YC and JK designed the study. JK supervised the research.

Corresponding author

Correspondence to Junya Kuroda.

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Conflict of interest

Y.F. is an employee of Nippon Shinyaku. J.K. has received research funding from Bristol-Myers Squibb, Sysmex, Celgene, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Kyowa Kirin, Chugai Pharmaceutical, Eisai, Astellas Pharma, Dainippon Sumitomo Pharma, Nippon Shinyaku, Takeda, Shionogi, Asahi Kasei, Daiichi Sankyo, MSD, Taiho Pharmaceutical, Fujimoto Pharmaceutical and Pfizer, has received honoraria from Bristol-Myers Squibb, Janssen Pharmaceutical K.K, Celgene Corporation, Ono Pharmaceutical, Takeda, Sanofi, Kyowa Kirin, Chugai Pharmaceutical, Eisai, Astellas Pharma, Nippon Shinyaku, Dainippon Sumitomo Pharma, Daiichi Sankyo, Fujimoto Pharmaceutical, Abbvie and Otsuka Pharmaceutical; and is a consultant for Janssen Pharmaceutical K.K, Celgene, Bristol-Myers Squibb, Sanofi and Abbvie. H.H. has received research funding from Celgene, Takeda, Ono Pharmaceutical, Kyowa Kirin, Sanofi, MSD, Chugai Pharmaceutical, Shionogi, Bayer, Eizai, and Astellas Pharma; has received honoraria from Janssen, Celgene, Takeda, Sanofi and Ono; and is a consultant for Janssen, Takeda and Celgene. M.T. has received research funding from Kyowa Kirin, Chugai Pharmaceutical, Eisai, and Astellas Pharma. T.K. has received honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, Eisai, and Nippon Shinyaku. T.T. has received research funding from Nippon Shinyaku. Others have no conflict of interest.

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Nishiyama, D., Chinen, Y., Isa, R. et al. EWSR1 overexpression is a pro-oncogenic event in multiple myeloma. Int J Hematol 113, 381–394 (2021). https://doi.org/10.1007/s12185-020-03027-0

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