A Knock-In Mouse Model of Thymoma With the GTF2I L424H Mutation.
Digital spatial profiling
GTF2I mutation
Mouse model
Thymic epithelial tumors
Journal
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
ISSN: 1556-1380
Titre abrégé: J Thorac Oncol
Pays: United States
ID NLM: 101274235
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
04
07
2022
accepted:
02
08
2022
pubmed:
2
9
2022
medline:
24
11
2022
entrez:
1
9
2022
Statut:
ppublish
Résumé
The pathogenesis of thymic epithelial tumors remains largely unknown. We previously identified GTF2I L424H as the most frequently recurrent mutation in thymic epithelial tumors. Nevertheless, 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 was performed using both mouse tissues and human thymic epithelial tumors. We observed that the Gtf2i mutation impairs development of the 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. Results of gene set variation assay analysis revealed that gene signatures of cortical thymic epithelial cells and thymic epithelial progenitor cells are also enriched in the thymomas of the knock-in mice, which mirrors the human counterparts in The Cancer Genome Atlas database. Immunohistochemistry 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.
Identifiants
pubmed: 36049655
pii: S1556-0864(22)01550-7
doi: 10.1016/j.jtho.2022.08.008
pmc: PMC9691559
mid: NIHMS1833283
pii:
doi:
Substances chimiques
GTF2I protein, human
0
Gtf2i protein, mouse
0
Transcription Factors, TFII
0
Transcription Factors, TFIII
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1375-1386Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011304
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2022 International Association for the Study of Lung Cancer. All rights reserved.
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