NPM–ALK-Induced Reprogramming of Mature TCR-Stimulated T Cells Results in Dedifferentiation and Malignant Transformation
| Autor: | Qian Zhang, John K. Everett, Hong Kong, Damian Maseda, Kelly Zullo, Fang Wei, James L. Riley, John W. Tobias, Mariusz A. Wasik, Jan M. Pawlicki, David L. Cookmeyer, Amanda A. Watkins, Hong Y. Wang, Frederic D. Bushman, Sarah Javaid, David M. Walter |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research T-Lymphocytes T cell Receptors Antigen T-Cell T-Cell Transformation Apoptosis Biology medicine.disease_cause Malignant transformation 03 medical and health sciences 0302 clinical medicine Tumor Cells Cultured medicine Humans Phosphorylation E2F PI3K/AKT/mTOR pathway Cell Proliferation TOR Serine-Threonine Kinases T-cell receptor Cell Dedifferentiation Protein-Tyrosine Kinases Cellular Reprogramming Cell biology Cell Transformation Neoplastic 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Lymphoma Large-Cell Anaplastic Carcinogenesis Reprogramming |
| Zdroj: | Cancer Research. 81:3241-3254 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-20-2297 |
| Popis: | Fusion genes including NPM–ALK can promote T-cell transformation, but the signals required to drive a healthy T cell to become malignant remain undefined. In this study, we introduce NPM–ALK into primary human T cells and demonstrate induction of the epithelial-to-mesenchymal transition (EMT) program, attenuation of most T-cell effector programs, reemergence of an immature epigenomic profile, and dynamic regulation of c-Myc, E2F, and PI3K/mTOR signaling pathways early during transformation. A mutant of NPM–ALK failed to bind several signaling complexes including GRB2/SOS, SHC1, SHC4, and UBASH3B and was unable to transform T cells. Finally, T-cell receptor (TCR)–generated signals were required to achieve T-cell transformation, explaining how healthy individuals can harbor T cells with NPM–ALK translocations. These findings describe the fundamental mechanisms of NPM–ALK-mediated oncogenesis and may serve as a model to better understand factors that regulate tumor formation. Significance: This investigation into malignant transformation of T cells uncovers a requirement for TCR triggering, elucidates integral signaling complexes nucleated by NPM–ALK, and delineates dynamic transcriptional changes as a T cell transforms. See related commentary by Spasevska and Myklebust, p. 3160 |
| Databáze: | OpenAIRE |
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