ALK Variants Differentially Modulate Neuroblastoma Tumor Behavior and Transcriptome in a Cellular Context-Dependent Manner

High-risk neuroblastoma remains a major clinical challenge despite intensive multimodal treatment. Alterations in the anaplastic lymphoma kinase ( ALK ) gene are frequent in NB and correlate with poor outcome. ALK ^-F1174L and ALK ^-R1275Q are the most prevalent activating mutations, but their specific effects on tumor behavior remain unclear. Here, we compared the impacts of ALK-wild-type (wt), ALK ^-F1174L and ALK ^-R1275Q in several NB xenograft models. In the SK-N-Be2c model, ALK ^-F1174L mediated numerous transcriptomic alterations without affecting tumor behavior. In GIMEN cells, only ALK ^-F1174L and ALK ^-R1275Q conferred tumorigenicity with distinct growth kinetics and transcriptional programs. In the mesenchymal SH-EP model, ALK variants induced distinct phenotypes, with ALK-wt and ALK ^-F1174L promoting partial transition toward neuroblastic identity. All ALK variants induced lung metastases, but with allele-specific dissemination patterns. Transcriptomic profiling of SH-EP tumors and corresponding metastases revealed partly opposing pathway regulation between ALK ^-F1174L and ALK ^-R1275Q . Overall, ALK variants differentially modulate NB behavior in a context-dependent manner.