The eukaryotic translation initiation factor eIF4E reprograms alternative splicing

Author:

Ghram Mehdi12ORCID,Morris Gavin12ORCID,Culjkovic‐Kraljacic Biljana12ORCID,Mars Jean‐Clement12ORCID,Gendron Patrick2ORCID,Skrabanek Lucy34,Revuelta Maria Victoria5ORCID,Cerchietti Leandro5ORCID,Guzman Monica L5,Borden Katherine L B12ORCID

Affiliation:

1. Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer University of Montreal Montreal QC Canada

2. Institute for Research in Immunology and Cancer (IRIC) Université de Montréal Montreal QC Canada

3. Department of Physiology and Biophysics, Institute for Computational Biomedicine Weill Cornell Medicine New York NY USA

4. Applied Bioinformatics Core Weill Cornell Medicine New York NY USA

5. Division of Hematology/Oncology, Department of Medicine Weill Cornell Medicine, Cornell University New York NY USA

Abstract

AbstractAberrant 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.

Funder

National Institutes of Health

Leukemia and Lymphoma Society

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

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