TY - JOUR
T1 - C-MYC regulates mRNA translation efficiency and start-site selection in lymphoma
AU - Singh, Kamini
AU - Lin, Jianan
AU - Zhong, Yi
AU - Burčul, Antonija
AU - Mohan, Prathibha
AU - Jiang, Man
AU - Sun, Liping
AU - Yong-Gonzalez, Vladimir
AU - Viale, Agnes
AU - Cross, Justin R.
AU - Hendrickson, Ronald C.
AU - Rätsch, Gunnar
AU - Ouyang, Zhengqing
AU - Wendel, Hans Guido
N1 - Funding Information:
H.-G. Wendel is supported by the National Institutes of Health grants RO1CA183876-03, R01CA207217-01, R01CA190384, and 5R01 1P50CA192937-01; the Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center (GC229409); the Lymphoma Research Foundation (GC227729); the Starr Cancer Consortium grant I10-0064; the Geoffrey Beene Cancer Research Center; Leukemia and Lymphoma Society Specialized Center of Research grant; New York State Stem Cell Science II IRP grant C028131; National Institutes of Health SPORE in Soft Tissue Sarcoma grant P50 CA217694; and the Memorial Sloan Kettering Cancer Center core grant (P30 CA008748). H.-G. Wendel is a scholar of the Leukemia and Lymphoma Society. G. Rätsch and Y. Zhong were supported by core funding of the Sloan Kettering Institute. G. Rätsch is supported by core funding of the Swiss Federal Institute of Technology in Zürich. Z. Ouyang is partially supported by National Institutes of Health/National Institute of General Medical Sciences grant R35 GM124998. We acknowledge the use of the Integrated Genomics Operation Core, funded by the National Cancer Institute Cancer Center Support Grant (P30 CA08748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. The authors declare no competing financial interests.
Funding Information:
We thank Anne Quy Hoa Le Thi (Johns Hopkins University School of Medicine, Baltimore, MD) for providing the P493-6 cell line. We thank Renier J. Brentjens (Memorial Sloan Kettering Cancer Center, New York, NY) for providing the CD19 CAR construct. We thank Massimo Caputi (Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL) for providing the c-DNA constructs for SRSF1. We also thank Liz Chang for expert technical assistance with LC-MS experiments. H.-G. Wendel is supported by the National Institutes of Health grants RO1CA183876-03, R01CA207217-01, R01CA190384, and 5R01 1P50CA192937-01; the Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center (GC229409); the Lymphoma Research Foundation (GC227729); the Starr Cancer Consortium grant I10-0064; the Geoffrey Beene Cancer Research Center; Leukemia and Lymphoma Society Specialized Center of Research grant; New York State Stem Cell Science II IRP grant C028131; National Institutes of Health SPORE in Soft Tissue Sarcoma grant P50 CA217694; and the Memorial Sloan Kettering Cancer Center core grant (P30 CA008748). H.-G. Wendel is a scholar of the Leukemia and Lymphoma Society. G. R?tsch and Y. Zhong were supported by core funding of the Sloan Kettering Institute. G. R?tsch is supported by core funding of the Swiss Federal Institute of Technology in Z?rich. Z. Ouyang is partially supported by National Institutes of Health/National Institute of General Medical Sciences grant R35 GM124998. We acknowledge the use of the Integrated Genomics Operation Core, funded by the National Cancer Institute Cancer Center Support Grant (P30 CA08748), Cycle for Survival, and the Marie-Jos?e and Henry R. Kravis Center for Molecular Oncology.
Publisher Copyright:
© 2019 Singh et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2019
Y1 - 2019
N2 - 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 59UTR 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.
AB - 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 59UTR 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.
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U2 - 10.1084/jem.20181726
DO - 10.1084/jem.20181726
M3 - Article
C2 - 31142587
AN - SCOPUS:85069265624
SN - 0022-1007
VL - 216
SP - 1509
EP - 1524
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
ER -