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J Exp Med. 2019 Jul 1;216(7):1509-1524. doi: 10.1084/jem.20181726. Epub 2019 May 29.

c-MYC regulates mRNA translation efficiency and start-site selection in lymphoma.

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY.
2
The Jackson Laboratory for Genomic Medicine, Farmington, CT.
3
Department of Biomedical Engineering, University of Connecticut, Storrs, CT.
4
Computational Biology Department, Memorial Sloan Kettering Cancer Center, New York, NY.
5
Integrated Genomics Operation, Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.
6
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY.
7
Proteomics and Microchemistry, Memorial Sloan- Kettering Cancer Center, New York, NY.
8
Computational Biology Department, Memorial Sloan Kettering Cancer Center, New York, NY raetsch@inf.ethz.ch.
9
Biomedical Informatics, Department of Computer Science, Swiss Federal Institute of Technology, Zürich, Switzerland.
10
The Jackson Laboratory for Genomic Medicine, Farmington, CT zhengqing.ouyang@jax.org.
11
Department of Genetics and Genome Sciences and Institute for System Genomics, University of Connecticut Health Center, Farmington, CT.
12
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY wendelh@mskcc.org.

Abstract

The oncogenic c-MYC (MYC) transcription factor has broad effects on gene expression and cell behavior. We show that MYC alters the efficiency and quality of mRNA translation into functional proteins. Specifically, MYC drives the translation of most protein components of the electron transport chain in lymphoma cells, and many of these effects are independent from proliferation. Specific interactions of MYC-sensitive RNA-binding proteins (e.g., SRSF1/RBM42) with 5'UTR sequence motifs mediate many of these changes. Moreover, we observe a striking shift in translation initiation site usage. For example, in low-MYC conditions, lymphoma cells initiate translation of the CD19 mRNA from a site in exon 5. This results in the truncation of all extracellular CD19 domains and facilitates escape from CD19-directed CAR-T cell therapy. Together, our findings reveal MYC effects on the translation of key metabolic enzymes and immune receptors in lymphoma cells.

PMID:
31142587
PMCID:
PMC6605752
[Available on 2020-01-01]
DOI:
10.1084/jem.20181726

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