Oncogenic NPM-ALK reprograms the TGM1 interactome toward oncogenic signaling and transcriptional states

Oncogenic NPM-ALK drives aberrant signaling networks that promote malignant phenotypes; however, the molecular mechanisms linking oncogenic signaling to downstream cellular programs remain incompletely understood. Among candidate regulatory factors, transglutaminase 1 (TGM1) has not been functionally characterized in this context. Here, we investigated the role of TGM1 in NPM-ALK–expressing cells by combining proximity-dependent proteomics with functional analyses. Using a TurboID- based approach, we mapped the TGM1-associated protein network and identified extensive remodeling of this network upon NPM-ALK expression. Proteomic analyses revealed that NPM-ALK reduced TGM1-associated proteins involved in genome maintenance and DNA repair, while enhancing associations with proteins linked to cytoplasmic translation and PI3K–AKT signaling pathways. Consistent with these findings, TGM1 deficiency impaired cell proliferation without significantly affecting cell viability, indicating a specific role in maximal proliferative capacity. Furthermore, proteomic and functional analyses suggested a link between TGM1 and AKT signaling pathways. Together, these findings suggest that oncogenic NPM-ALK reprograms the TGM1 interactome toward oncogenic signaling and transcriptional states, positioning TGM1 within signaling networks associated with proliferative cellular phenotypes.