Abstract
The pathogenesis of thymic epithelial tumors (TETs) is poorly understood. Recently we reported the frequent occurrence of a missense mutation in the GTF2I gene in TETs and hypothesized that GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the transcriptome of normal thymic epithelial cells and upregulated several oncogenic genes. Gtf2i L424H knockin cells exhibited cell transformation, aneuploidy, and increase tumor growth and survival under glucose deprivation or DNA damage. Gtf2i mutation also increased the expression of several glycolytic enzymes, cyclooxygenase-2, and caused modifications of lipid metabolism. Elevated cyclooxygenase-2 expression by Gtf2i mutation was required for survival under metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I mutation as a new oncogenic driver that is responsible for transformation of thymic epithelial cells.
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Acknowledgements
We acknowledge the assistance provided by the Flow Cytometry and Proteomics & Metabolomics Shared Resource of Lombardi Comprehensive Cancer Center for FACS and Metabolomics. We would like to thank Dr. Uimook Choi (NIAID, NIH) and Jung-hyun Kim (NCI, NIH) for valuable discussions on CRISPR system. This work was supported by Lombardi Comprehensive Cancer Center grant (P30-CA051008 to GG).
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Conceptualization, I-KK, YW, Y-WZ and GG; methodology, I-KK, YW, and Y-WZ; validation, I-KK, GR and XZ; formal analysis, I-KK and RF; investigation and data curation, I-KK; writing—original draft, I-KK; writing—review and editing, I-KK, GR, XZ, RF, YW, MLA, Y-WZ and GG.
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Kim, IK., Rao, G., Zhao, X. et al. Mutant GTF2I induces cell transformation and metabolic alterations in thymic epithelial cells. Cell Death Differ 27, 2263–2279 (2020). https://doi.org/10.1038/s41418-020-0502-7
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DOI: https://doi.org/10.1038/s41418-020-0502-7
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