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A Knock-in Mouse Model of Thymoma with the GTF2I L424H Mutation

  1. Author:
    He, Yongfeng
    Kim, In-Kyu
    Bian, Jing
    Polyzos, Alexander
    Di Giammartino, Dafne Campigli
    Zhang, Yuwen
    Luo, Ji
    Hernandez, Maria O
    Kedei, Noemi
    Cam, Maggie
    Borczuk, Alain C
    Lee, Trevor
    Han, Yumin
    Conner, Elizabeth A
    Wong, Madeline M F
    Tillo, Desiree C
    Umemura, Shigeki
    Chen, Vincent
    Ruan, Lydia
    White, Jessica B
    Miranda, Ileana C
    Awasthi,Roackie
    Altorki, Nasser K
    Divakar, Prajan
    Elemento, Olivier
    Apostolou, Effie
    Giaccone, Giuseppe

  2. Author Address

    Meyer Cancer Center, Weill Cornel Medicine, New York, NY10065, USA., Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC20057, USA., CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC20057, USA; New address: Department of Cell Biology, University of Virginia, School of Medicine, Charlottesville, VA 22908, USA., Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA., Collaborative Protein Technology Resource, Office of Science and Technology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Department of Pathology, Sandra and Edward Meyer Cancer Center, Weill Cornel Medicine, New York, NY10065, USA; New Address: Department of Pathology, Northwell Health, Greenvale, NY11548, USA., CCR Genomics Core, National Cancer Institute, Bethesda, MD 20892, USA., Caryl and Israel Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY10065, USA., Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University, New York, NY 10065, USA., Frederick National Laboratory for Cancer Research, Laboratory Animal Sciences, Mouse Modeling & Cryopreservation, National Cancer Institute, Frederick, MD 21701, USA., Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY10065, USA., NanoString 174; Technologies Inc., Seattle, WA 98109, USA., Meyer Cancer Center, Weill Cornel Medicine, New York, NY10065, USA; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC20057, USA. Electronic address: gig4001@med.cornell.edu.,
    1. Year: 2022
    2. Date: Aug 29
    3. Epub Date: 2022 08 29
  2. Journal: Journal of Thoracic Oncology : official publication of the International Association for the Study of Lung Cancer
    1. 17
    2. 12
    3. Pages: 1375-1386
  4. Type of Article: Article
  1. Abstract:

    The pathogenesis of thymic epithelial tumors remains largely unknown. We previously identified GTF2I L424H as the most frequently recurrent mutation in thymic epithelial tumors. However, the precise role of this mutation in tumorigenesis of thymic epithelial cells is unclear. To investigate the role of GTF2I L424H mutation in thymic epithelial cells in vivo, we generated and characterized a mouse model in which the Gtf2i L424H mutation was conditionally knocked-in in the Foxn1+ thymic epithelial cells. Digital spatial profiling was performed on thymomas and normal thymic tissues with GeoMx-mouse whole transcriptome atlas. Immunohistochemistry staining (IHC) was performed using both mouse tissues and human thymic epithelial tumors. We observed that the Gtf2i mutation impairs development of thymic medulla and maturation of medullary thymic epithelial cells in young mice and causes tumor formation in the thymus of aged mice. Cell cycle related pathways, such as E2F targets and MYC targets are enriched in the tumor epithelial cells. GSVA analysis demonstrated that gene signatures of cortical thymic epithelial cells and thymic epithelial progenitor cells are also enriched in thymomas of the KI mice, which mirrors the human counterparts in the TCGA database. IHC results revealed similar expression pattern of epithelial cell markers between mouse and human thymomas. We have developed and characterized a novel thymoma mouse model. This study improves knowledge of the molecular drivers in thymic epithelial cells and provides a tool for further study of the biology of thymic epithelial tumors and for development of novel therapies. Copyright © 2022 International Association for the Study of Lung Cancer. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.jtho.2022.08.008
  3. PMID: 36049655
  4. View record in Web of Science®
  5. WOS: 000892531300007
  6. PII : S1556-0864(22)01550-7

Library Notes

  1. Fiscal Year: FY2021-2022
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