Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most aggressive non-Hodgkin lymphoma (NHL), accounting for about 31% of the newly diagnosed NHL worldwide. Although approximately 60% of patients who initially received a standard R-CHOP treatment likely have a 3-year event-free survival, many patients become refractory or relapsed due to the genetic heterogeneity of this malignancy. Hence, new treatment strategies are urgently needed. MEF2C, a member of the MEF2 transcription factor family gene, plays great important roles involved in the development of various tissues and the pathogenesis of lymphoma. However, the exact functions and molecular mechanisms of MEF2C in DLBCL are not fully investigated. By Sanger sequencing, we identified a novel point mutation of MEF2C at the p.N389 site in DLBCL patient, which was further validated by several DLBCL cell lines. Intriguingly, we found that the p.N389S mutation did not influence MEF2C expression, protein stability, and subcellular distribution, but enhanced its transcriptional activity. Furthermore, we demonstrated that MEF2C p.N389S mutation promotes DLBCL cell proliferation, cellular adhesion, and tumor formation in nude mice. On mechanism, our data revealed that MEF2C p.N389S mutation increases c-JUN expression, and c-JUN regulation mediated the oncogenic function of MEF2C p.N389S mutation on DLBCL cells. Our finding may provide a significant insight into the DLBCL and a compelling therapy target for this disease treatment.
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Yuan Chunluan designed research and wrote the paper; Zhao Jingjing, Miao Lei, Zhang Jie, Cao Sha, Hu Yapeng, and Zhang Weimin performed research and analyzed data. All authors read and approved the manuscript.
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Patients were diagnosed according to the criteria of the World Health Organization classification of hematological malignancies. Before the initiation of treatment, the clinical features, including Mantle Cell Lymphoma International Prognostic Index (MIPI) score, lactate dehydrogenase (LDH) content in serum, performance status (determined using Eastern Cooperative Oncology Group performance status scores) and white blood cell (WBC) counts, were collected. All experimental protocols and procedures involved in the present study were approved by the Ethics Committee of the First People's Hospital of Lianyungang. Written informed consent was obtained from all participates for publication of this article.
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Jingjing, Z., Lei, M., Jie, Z. et al. A novel MEF2C mutation in lymphoid neoplasm diffuse large B-cell lymphoma promotes tumorigenesis by increasing c-JUN expression. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1549–1558 (2020). https://doi.org/10.1007/s00210-019-01764-6
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DOI: https://doi.org/10.1007/s00210-019-01764-6