Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma Article Swipe
Hector H. Huang
,
Ian Ferguson
,
Alexis M. Thornton
,
Prabhakar Bastola
,
Christine Lam
,
Yu-Hsiu T. Lin
,
Priya Choudhry
,
Margarette C. Mariano
,
Makeba Marcoulis
,
Chin Fen Teo
,
Julia Malato
,
Paul Phojanakong
,
Thomas G. Martin
,
Jeffrey L. Wolf
,
Sandy W. Wong
,
Nina Shah
,
Byron Hann
,
Angela N. Brooks
,
Arun P. Wiita
·
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-020-15521-4
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-020-15521-4
Enhancing the efficacy of proteasome inhibitors (PI) is a central goal in myeloma therapy. We proposed that signaling-level responses after PI may reveal new mechanisms of action that can be therapeutically exploited. Unbiased phosphoproteomics after treatment with the PI carfilzomib surprisingly demonstrates the most prominent phosphorylation changes on splicing related proteins. Spliceosome modulation is invisible to RNA or protein abundance alone. Transcriptome analysis after PI demonstrates broad-scale intron retention, suggestive of spliceosome interference, as well as specific alternative splicing of protein homeostasis machinery components. These findings lead us to evaluate direct spliceosome inhibition in myeloma, which synergizes with carfilzomib and shows potent anti-tumor activity. Functional genomics and exome sequencing further support the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.
Related Topics
Concepts
Spliceosome
RNA splicing
Carfilzomib
Biology
Cell biology
Transcriptome
Proteasome inhibitor
Proteasome
Computational biology
Genetics
RNA
Gene expression
Gene
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1038/s41467-020-15521-4
- https://www.nature.com/articles/s41467-020-15521-4.pdf
- OA Status
- gold
- Cited By
- 44
- References
- 70
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W3018581552
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W3018581552Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1038/s41467-020-15521-4Digital Object Identifier
- Title
-
Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myelomaWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2020Year of publication
- Publication date
-
2020-04-22Full publication date if available
- Authors
-
Hector H. Huang, Ian Ferguson, Alexis M. Thornton, Prabhakar Bastola, Christine Lam, Yu-Hsiu T. Lin, Priya Choudhry, Margarette C. Mariano, Makeba Marcoulis, Chin Fen Teo, Julia Malato, Paul Phojanakong, Thomas G. Martin, Jeffrey L. Wolf, Sandy W. Wong, Nina Shah, Byron Hann, Angela N. Brooks, Arun P. WiitaList of authors in order
- Landing page
-
https://doi.org/10.1038/s41467-020-15521-4Publisher landing page
- PDF URL
-
https://www.nature.com/articles/s41467-020-15521-4.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.nature.com/articles/s41467-020-15521-4.pdfDirect OA link when available
- Concepts
-
Spliceosome, RNA splicing, Carfilzomib, Biology, Cell biology, Transcriptome, Proteasome inhibitor, Proteasome, Computational biology, Genetics, RNA, Gene expression, GeneTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
44Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 1, 2024: 7, 2023: 10, 2022: 12, 2021: 8Per-year citation counts (last 5 years)
- References (count)
-
70Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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