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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
PMID: 33619116 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.