This is an archive of papers published by the staff and faculty of Fox Chase Cancer Center. For questions about content, please contact Talbot Research Library
Last updated on
Pawlicki JM , Cookmeyer DL , Maseda D , Everett JK , Wei F , Kong H , Zhang Q , Wang HY , Tobias JW , Walter DM , Zullo KM , Javaid S , Watkins A , Wasik MA , Bushman FD , Riley JL
NPM-ALK induces reprogramming of mature TCR-stimulated T cells resulting in de-differentiation and malignant transformation
Cancer Res. 2021 Feb 22;81(12) :3241-3254
PMID: 33619116 PMCID: PMC8260452 URL: https://www.ncbi.nlm.nih.gov/pubmed/33619116
AbstractFusion 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, re-emergence 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. Lastly, 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.
Notes1538-7445 Pawlicki, Jan M Cookmeyer, David L Maseda, Damian Orcid: 0000-0003-0722-6881 Everett, John K Wei, Fang Orcid: 0000-0001-8964-1645 Kong, Hong Zhang, Qian Wang, Hong Y Tobias, John W Orcid: 0000-0002-5362-7013 Walter, David M Zullo, Kelly M Javaid, Sarah Watkins, Amanda Wasik, Mariusz A Bushman, Frederic D Riley, James L Orcid: 0000-0002-1057-576x Journal Article United States Cancer Res. 2021 Feb 22:canres.2297.2020. doi: 10.1158/0008-5472.CAN-20-2297.