The eukaryotic translation initiation factor eIF4E reprograms alternative splicing.
acute myeloid leukemia
eIF4E
splicing
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
03 04 2023
03 04 2023
Historique:
revised:
30
01
2023
received:
20
12
2021
accepted:
31
01
2023
medline:
4
4
2023
pubmed:
28
2
2023
entrez:
27
2
2023
Statut:
ppublish
Résumé
Aberrant splicing is typically attributed to splice-factor (SF) mutation and contributes to malignancies including acute myeloid leukemia (AML). Here, we discovered a mutation-independent means to extensively reprogram alternative splicing (AS). We showed that the dysregulated expression of eukaryotic translation initiation factor eIF4E elevated selective splice-factor production, thereby impacting multiple spliceosome complexes, including factors mutated in AML such as SF3B1 and U2AF1. These changes generated a splicing landscape that predominantly supported altered splice-site selection for ~800 transcripts in cell lines and ~4,600 transcripts in specimens from high-eIF4E AML patients otherwise harboring no known SF mutations. Nuclear RNA immunoprecipitations, export assays, polysome analyses, and mutational studies together revealed that eIF4E primarily increased SF production via its nuclear RNA export activity. By contrast, eIF4E dysregulation did not induce known SF mutations or alter spliceosome number. eIF4E interacted with the spliceosome and some pre-mRNAs, suggesting its direct involvement in specific splicing events. eIF4E induced simultaneous effects on numerous SF proteins, resulting in a much larger range of splicing alterations than in the case of mutation or dysregulation of individual SFs and providing a novel paradigm for splicing control and dysregulation.
Identifiants
pubmed: 36843541
doi: 10.15252/embj.2021110496
pmc: PMC10068332
doi:
Substances chimiques
RNA Splicing Factors
0
Eukaryotic Initiation Factor-4E
0
Eukaryotic Initiation Factors
0
Banques de données
GEO
['GSE158728', 'GSE67040']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e110496Subventions
Organisme : NCI NIH HHS
ID : R01 CA080728
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA098571
Pays : United States
Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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