In-depth analysis of alternative splicing landscape in multiple myeloma and potential role of dysregulated splicing factors.
Journal
Blood cancer journal
ISSN: 2044-5385
Titre abrégé: Blood Cancer J
Pays: United States
ID NLM: 101568469
Informations de publication
Date de publication:
20 12 2022
20 12 2022
Historique:
received:
07
09
2022
accepted:
22
11
2022
revised:
09
11
2022
entrez:
19
12
2022
pubmed:
20
12
2022
medline:
22
12
2022
Statut:
epublish
Résumé
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/ .
Identifiants
pubmed: 36535935
doi: 10.1038/s41408-022-00759-6
pii: 10.1038/s41408-022-00759-6
pmc: PMC9763261
doi:
Substances chimiques
RNA Splicing Factors
0
SRSF1 protein, human
0
Serine-Arginine Splicing Factors
170974-22-8
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
171Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA100707
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA155258
Pays : United States
Organisme : BLRD VA
ID : I01 BX001584
Pays : United States
Informations de copyright
© 2022. The Author(s).
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