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Genetics and Genomics

Dysregulation of alternative splicing contributes to multiple myeloma pathogenesis

British Journal of Cancer volume 128, pages 1086–1094 (2023)Cite this article

Subjects

Abstract

Background

Dysregulation of alternative splicing (AS) triggers many tumours, understanding the roles of splicing events during tumorigenesis would open new avenues for therapies and prognosis in multiple myeloma (MM).

Methods

Molecular, genetic, bioinformatic and statistic approaches are used to determine the mechanism of the candidate splicing factor (SF) in myeloma cell lines, myeloma xenograft models and MM patient samples.

Results

GSEA reveals a significant difference in the expression pattern of the alternative splicing pathway genes, notably enriched in MM patients. Upregulation of the splicing factor SRSF1 is observed in the progression of plasma cell dyscrasias and predicts MM patients’ poor prognosis. The c-indices of the Cox model indicated that SRSF1 improved the prognostic stratification of MM patients. Moreover, SRSF1 knockdown exerts a broad anti-myeloma activity in vitro and in vivo. The upregulation of SRSF1 is caused by the transcription factor YY1, which also functions as an oncogene in myeloma cells. Through RNA-Seq, we systematically verify that SRSF1 promotes the tumorigenesis of myeloma cells by switching AS events.

Conclusion

Our results emphasise the importance of AS for promoting tumorigenesis of MM. The candidate SF might be considered as a valuable therapeutic target and a potential prognostic biomarker for MM.

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Fig. 1: Aberrant alternative splicing in MM.
Fig. 2: SRSF1 increases tumorigenic potentials of MM.
Fig. 3: SRSF1 is positively regulated by the transcription factor YY1.
Fig. 4: Dysregulated YY1 promotes myeloma progression and is associated with a poor prognosis.
Fig. 5: Global landscape alternative splicing events regulated by SRSF1.

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Data availability

The data generated in this study are publicly available in Gene Expression Omnibus (GEO) at GSE160724. Other detailed assays are available in the supplemental methods. The data supporting the findings of this study can be found in the article, or available from the corresponding author upon reasonable request.

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Funding

The research leading to these results has received funding from the National Natural Science Foundation of China (82270197, 82270211), Natural Science Foundation of Jiangsu Province China (BK20201408), The special project of “Technological innovation” project of CNNC Medical Industry Co. Ltd.) (ZHYLYB2021002), Jiangsu Social Development Project—New Clinical Diagnosis and Treatment Technology (BE2019664).

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Author notes

  1. These authors contributed equally: Sha Song, Weimin Zhang.

Authors and Affiliations

  1. Department of Cell Biology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China

    Sha Song, Zhiming Wang, Qi Su & Wenzhuo Zhuang

  2. Department of Hematology, the Second Affiliated Hospital of Soochow University, Suzhou, China

    Weimin Zhang, Qi Li, Xinyun Zhang & Bingzong Li

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  1. Sha Song
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Contributions

W Zhuang and BL designed the research, SS and W Zhang performed the research, JL and QL wrote the paper, ZW, Qi Su and XZ performed the research and modified the paper.

Corresponding authors

Correspondence to Bingzong Li or Wenzhuo Zhuang.

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Song, S., Zhang, W., Li, Q. et al. Dysregulation of alternative splicing contributes to multiple myeloma pathogenesis. Br J Cancer 128, 1086–1094 (2023). https://doi.org/10.1038/s41416-022-02124-7

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