Data from NPM–ALK-Induced Reprogramming of Mature TCR-Stimulated T Cells Results in Dedifferentiation and Malignant Transformation

• DOI: 10.1158/0008-5472.c.6513093
• Publication Date: 2024-03-12T22:48:25Z
• Authors: Jan M. Pawlicki; David L. Cookmeyer; Damian Maseda; John K. Everett; Fang Wei; Hong Kong; Qian Zhang; Hong Y. Wang; John W. Tobias; David M. Walter; Kelly M. Zullo; Sarah Javaid; Amanda Watkins; Mariusz A. Wasik; Frederic D. Bushman; James L. Riley
• Keywords: Reprogramming; Malignant Transformation

<div>Abstract<p>Fusion genes including NPM–ALK can promote T-cell transformation, but the signals required to drive a healthy T cell become malignant remain undefined. In this study, we introduce into primary human cells and demonstrate induction of epithelial-to-mesenchymal transition (EMT) program, attenuation most effector programs, reemergence an immature epigenomic profile, dynamic regulation c-Myc, E2F, PI3K/mTOR signaling pathways early during transformation. A mutant failed bind several complexes GRB2/SOS, SHC1, SHC4, UBASH3B was unable transform cells. Finally, receptor (TCR)–generated were achieve explaining how individuals harbor with translocations. These findings describe fundamental mechanisms NPM–ALK-mediated oncogenesis may serve as model better understand factors that regulate tumor formation.</p>Significance:<p>This investigation transformation uncovers requirement for TCR triggering, elucidates integral nucleated by NPM–ALK, delineates transcriptional changes transforms.</p><p><i>See related commentary Spasevska Myklebust, p. 3160</i></p></div>