In-depth analysis of alternative splicing landscape in multiple myeloma and potential role of dysregulated splicing factors Journal Article
| Authors: | Aktas Samur, A.; Fulciniti, M.; Avet-Loiseau, H.; Lopez, M. A.; Derebail, S.; Corre, J.; Minvielle, S.; Magrangeas, F.; Moreau, P.; Anderson, K. C.; Parmigiani, G.; Samur, M. K.; Munshi, N. C. |
| Article Title: | In-depth analysis of alternative splicing landscape in multiple myeloma and potential role of dysregulated splicing factors |
| Abstract: | Splicing changes are common in cancer and are associated with dysregulated splicing factors. Here, we analyzed RNA-seq data from 323 newly diagnosed multiple myeloma (MM) patients and described the alternative splicing (AS) landscape. We observed a large number of splicing pattern changes in MM cells compared to normal plasma cells (NPC). The most common events were alterations of mutually exclusive exons and exon skipping. Most of these events were observed in the absence of overall changes in gene expression and often impacted the coding potential of the alternatively spliced genes. To understand the molecular mechanisms driving frequent aberrant AS, we investigated 115 splicing factors (SFs) and associated them with the AS events in MM. We observed that ~40% of SFs were dysregulated in MM cells compared to NPC and found a significant enrichment of SRSF1, SRSF9, and PCB1 binding motifs around AS events. Importantly, SRSF1 overexpression was linked with shorter survival in two independent MM datasets and was correlated with the number of AS events, impacting tumor cell proliferation. Together with the observation that MM cells are vulnerable to splicing inhibition, our results may lay the foundation for developing new therapeutic strategies for MM. We have developed a web portal that allows custom alternative splicing event queries by using gene symbols and visualizes AS events in MM and subgroups. Our portals can be accessed at http://rconnect.dfci.harvard.edu/mmsplicing/ and https://rconnect.dfci.harvard.edu/mmleafcutter/. © 2022, The Author(s). |
| Keywords: | adult; cancer survival; controlled study; aged; human cell; major clinical study; exon; genetics; exons; nonhuman; cancer patient; cell proliferation; mouse; gene overexpression; proteasome; multiple myeloma; x box binding protein 1; protein depletion; protein protein interaction; animal experiment; animal model; genetic association; in vitro study; fluorescence in situ hybridization; protein processing; messenger rna; western blotting; alternative splicing; alternative rna splicing; dna sequence; spliceosome; dna binding; histone deacetylase; nucleotide; membrane cofactor protein; heterodimerization; b lymphocyte activation; ectopic expression; humans; human; male; female; article; rna sequencing; exon skipping; stat2 protein; differential expression analysis; rna-binding domain; interferon regulatory factor 9; rna splicing factor; deubiquitination; rna splicing factors; rna recognition motif; serine arginine rich splicing factor; bcr signaling; gene network analysis; srsf1 protein, human; kms-11 cell line; serine-arginine splicing factors |
| Journal Title: | Blood Cancer Journal |
| Volume: | 12 |
| Issue: | 12 |
| ISSN: | 2044-5385 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-12-20 |
| Start Page: | 171 |
| Language: | English |
| DOI: | 10.1038/s41408-022-00759-6 |
| PUBMED: | 36535935 |
| PROVIDER: | scopus |
| PMCID: | PMC9763261 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 January 2023 -- Source: Scopus |
