NPM-ALK induces reprogramming of mature TCR-stimulated T cells resulting in de-differentiation and malignant transformation

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. By introducing NPM-ALK into primary human T cells, we show induction of the epithelial-to-mesenchymal transition (EMT) program, downregulation of T cell effector programs and function, re-emergence of an immature T cell’s epigenomic profile , and dynamic regulation of c-Myc, E2F, and PI3K/mTOR signaling pathways early during transformation. We identify a mutant of NPM-ALK that fails to bind several signaling complexes including GRB2/SOS, SHC1, SHC4, and UBASH3B and is unable to transform T cells. Lastly, we demonstrate that TCR-generated signals are required to achieve T cell transformation, explaining how healthy individuals can harbor T cells with NPM-ALK translocations.